bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2024–04–28
43 papers selected by
Chun-Chi Chang, Universitäts Spital Zürich
  1. The causes and consequences of trained immunity in myeloid cells.
  2. Deciphering Staphylococcus aureus-host dynamics using dual activity-based protein profiling of ATP-interacting proteins.
  3. Streptococcus pneumoniae endopeptidase O induces trained immunity against numerous pathogen infections, a key role for G-CSF.
  4. Staphylococcus aureus Infections and Human Intestinal Microbiota.
  5. How Does Airway Surface Liquid Composition Vary in Different Pulmonary Diseases, and How Can We Use This Knowledge to Model Microbial Infections?
  6. Apolipoprotein E controls Dectin-1-dependent development of monocyte-derived alveolar macrophages upon pulmonary β-glucan-induced inflammatory adaptation.
  7. Activation of the RIG-I/MAVS Signaling Pathway during Human Adenovirus Type 3 Infection Impairs the Pro-Inflammatory Response Induced by Secondary Infection with Staphylococcus aureus.
  8. Macrophage polarization: an important role in inflammatory diseases.
  9. Lytic bacteriophages induce the secretion of antiviral and proinflammatory cytokines from human respiratory epithelial cells.
  10. Establishment of an in vitro model of monocyte-like THP-1 cells for trained immunity induced by bacillus Calmette-Guérin.
  11. PPARγ attenuates cellular senescence of alveolar macrophages in asthma-COPD overlap.
  12. Mucus polymer concentration and in vivo adaptation converge to define the antibiotic response of Pseudomonas aeruginosa during chronic lung infection.
  13. Ischemia does not provoke the full immune training repertoire in human cardiac fibroblasts.
  14. Macrophage niche imprinting as a determinant of macrophage identity and function.
  15. Vaccines Induce Homeostatic Immunity, Generating Several Secondary Benefits.
  16. Neutrophil Elastase Degrades Histone Deacetylases and Sirtuin 1 in Primary Human Monocyte Derived Macrophages.
  17. Single-Cell Analysis Uncovers Striking Cellular Heterogeneity of Lung-Infiltrating Regulatory T Cells during Eosinophilic versus Neutrophilic Allergic Airway Inflammation.
  18. Induction of ferroptosis: A new strategy for the control of bacterial infections.
  19. Repair and regeneration of the alveolar epithelium in lung injury.
  20. Exploring the role of CITED transcriptional regulators in the control of macrophage polarization.
  21. Bacterial diversity dominates variable macrophage responses of tuberculosis patients in Tanzania.
  22. Molecular Mechanisms of Lacticaseibacillus rhamnosus, LGG® Probiotic Function.
  23. A 30-color spectral flow cytometry panel for comprehensive analysis of immune cell composition and macrophage subsets in mouse metabolic organs.
  24. Novel Fermentates Can Enhance Key Immune Responses Associated with Viral Immunity.
  25. S100A8/9 modulates perturbation and glycolysis of macrophages in allergic asthma mice.
  26. IL-23 regulation of myeloid cell biology during inflammation.
  27. Bacterium-like Particles from Corynebacterium pseudodiphtheriticum as Mucosal Adjuvant for the Development of Pneumococcal Vaccines.
  28. Lactobacillus Reuteri Vesicles Regulate Mitochondrial Function of Macrophages to Promote Mucosal and Cutaneous Wound Healing.
  29. SERS Microsensors for the Study of pH Regulation in Cystic Fibrosis Patient-Derived Airway Cultures.
  30. Generation of human alveolar epithelial type I cells from pluripotent stem cells.
  31. In vitro platform to model the function of ionocytes in the human airway epithelium.
  32. Lower airway microbiota compositions differ between influenza, COVID-19 and bacteria-related acute respiratory distress syndromes.
  33. Upper respiratory microbial communities of healthy populations are shaped by niche and age.
  34. Antibiotics within first year are linked to infant gut microbiome disruption and elevated atopic dermatitis risk.
  35. Epithelial stem cells and niches in lung alveolar regeneration and diseases.
  36. Exploring Memory Function Beyond Immune Cells: ANGPTL4-Mediated Memory Functions in Tissue Resident Stem Cells.
  37. Microbiota metabolism of intestinal amino acids impacts host nutrient homeostasis and physiology.
  38. Mitochondrial-dependent oxidative phosphorylation is key for postnatal metabolic adaptation of alveolar macrophages in the lung.
  39. Advancing immunotherapy using biomaterials to control tissue, cellular, and molecular level immune signaling in skin.
  40. Meeting report 'Microbiology 2023: from single cell to microbiome and host', an international interacademy conference in Würzburg.
  41. Periportal macrophages protect against commensal-driven liver inflammation.
  42. IL-10 dependent adaptation allows macrophages to adjust inflammatory responses to TLR4 stimulation history.
  43. The effect of probiotic Bifidobacterium lactis Bl-04 on innate antiviral responses invitro.
  1. Front Immunol. 2024 ;15 1365127
    The causes and consequences of trained immunity in myeloid cells.
    Gunapati Bhargavi, Selvakumar Subbian.
      Conventionally, immunity in humans has been classified as innate and adaptive, with the concept that only the latter type has an immunological memory/recall response against specific antigens or pathogens. Recently, a new concept of trained immunity (a.k.a. innate memory response) has emerged. According to this concept, innate immune cells can exhibit enhanced responsiveness to subsequent challenges, after initial stimulation with antigen/pathogen. Thus, trained immunity enables the innate immune cells to respond robustly and non-specifically through exposure or re-exposure to antigens/infections or vaccines, providing enhanced resistance to unrelated pathogens or reduced infection severity. For example, individuals vaccinated with BCG to protect against tuberculosis were also protected from malaria and SARS-CoV-2 infections. Epigenetic modifications such as histone acetylation and metabolic reprogramming (e.g. shift towards glycolysis) and their inter-linked regulations are the key factors underpinning the immune activation of trained cells. The integrated metabolic and epigenetic rewiring generates sufficient metabolic intermediates, which is crucial to meet the energy demand required to produce proinflammatory and antimicrobial responses by the trained cells. These factors also determine the efficacy and durability of trained immunity. Importantly, the signaling pathways and regulatory molecules of trained immunity can be harnessed as potential targets for developing novel intervention strategies, such as better vaccines and immunotherapies against infectious (e.g., sepsis) and non-infectious (e.g., cancer) diseases. However, aberrant inflammation caused by inappropriate onset of trained immunity can lead to severe autoimmune pathological consequences, (e.g., systemic sclerosis and granulomatosis). In this review, we provide an overview of conventional innate and adaptive immunity and summarize various mechanistic factors associated with the onset and regulation of trained immunity, focusing on immunologic, metabolic, and epigenetic changes in myeloid cells. This review underscores the transformative potential of trained immunity in immunology, paving the way for developing novel therapeutic strategies for various infectious and non-infectious diseases that leverage innate immune memory.
    Keywords:  animal models; cell signaling; epigenetics; inflammation; innate immunity; macrophage; metabolism; neutrophil
    DOI:  https://doi.org/10.3389/fimmu.2024.1365127
  2. mSystems. 2024 Apr 24. e0017924
    Deciphering Staphylococcus aureus-host dynamics using dual activity-based protein profiling of ATP-interacting proteins.
    Stephen Dela Ahator, Kristin Hegstad, Christian S Lentz, Mona Johannessen.
      The utilization of ATP within cells plays a fundamental role in cellular processes that are essential for the regulation of host-pathogen dynamics and the subsequent immune response. This study focuses on ATP-binding proteins to dissect the complex interplay between Staphylococcus aureus and human cells, particularly macrophages (THP-1) and keratinocytes (HaCaT), during an intracellular infection. A snapshot of the various protein activity and function is provided using a desthiobiotin-ATP probe, which targets ATP-interacting proteins. In S. aureus, we observe enrichment in pathways required for nutrient acquisition, biosynthesis and metabolism of amino acids, and energy metabolism when located inside human cells. Additionally, the direct profiling of the protein activity revealed specific adaptations of S. aureus to the keratinocytes and macrophages. Mapping the differentially activated proteins to biochemical pathways in the human cells with intracellular bacteria revealed cell-type-specific adaptations to bacterial challenges where THP-1 cells prioritized immune defenses, autophagic cell death, and inflammation. In contrast, HaCaT cells emphasized barrier integrity and immune activation. We also observe bacterial modulation of host processes and metabolic shifts. These findings offer valuable insights into the dynamics of S. aureus-host cell interactions, shedding light on modulating host immune responses to S. aureus, which could involve developing immunomodulatory therapies.
    IMPORTANCE: This study uses a chemoproteomic approach to target active ATP-interacting proteins and examines the dynamic proteomic interactions between Staphylococcus aureus and human cell lines THP-1 and HaCaT. It uncovers the distinct responses of macrophages and keratinocytes during bacterial infection. S. aureus demonstrated a tailored response to the intracellular environment of each cell type and adaptation during exposure to professional and non-professional phagocytes. It also highlights strategies employed by S. aureus to persist within host cells. This study offers significant insights into the human cell response to S. aureus infection, illuminating the complex proteomic shifts that underlie the defense mechanisms of macrophages and keratinocytes. Notably, the study underscores the nuanced interplay between the host's metabolic reprogramming and immune strategy, suggesting potential therapeutic targets for enhancing host defense and inhibiting bacterial survival. The findings enhance our understanding of host-pathogen interactions and can inform the development of targeted therapies against S. aureus infections.
    Keywords:  ATP-interacting proteins; HaCaT cells; Staphylococcus aureus; THP-1 cells; activity-based protein profiling (ABPP); bacterial metabolism; host immune response; host–pathogen interactions
    DOI:  https://doi.org/10.1128/msystems.00179-24
  3. Clin Immunol. 2024 Apr 23. pii: S1521-6616(24)00117-7. [Epub ahead of print] 110226
    Streptococcus pneumoniae endopeptidase O induces trained immunity against numerous pathogen infections, a key role for G-CSF.
    Wenlong Xu, Yuan Yuan, Zhaoche Shu, Ting Guo, Bichen Liu, Jiangming Xiao, Lian Li, Yibin Yin, Xuemei Zhang.
      Antibiotic resistance and the surge of infectious diseases during the pandemic present significant threats to human health. Trained immunity emerges as a promising and innovative approach to address these infections. Synthetic or natural fungal, parasitic and viral components have been reported to induce trained immunity. However, it is not clear whether bacterial virulence proteins can induce protective trained immunity. Our research demonstrates Streptococcus pneumoniae virulence protein PepO, is a highly potent trained immunity inducer for combating broad-spectrum infection. Our findings showcase that rPepO training confers robust protection to mice against various pathogenic infections by enhancing macrophage functionality. rPepO effectively re-programs macrophages, re-configures their epigenetic modifications and bolsters their immunological responses, which is independent of T or B lymphocytes. In vivo and in vitro experiments confirm that trained macrophage-secreted complement C3 activates peritoneal B lymphocyte and enhances its bactericidal capacity. In addition, we provide the first evidence that granulocyte colony-stimulating factor (G-CSF) derived from trained macrophages plays a pivotal role in shaping central-trained immunity. In summation, our research demonstrates the capability of rPepO to induce both peripheral and central trained immunity in mice, underscoring its potential application in broad-spectrum anti-infection therapy. Our research provides a new molecule and some new target options for infectious disease prevention.
    Keywords:  B lymphocyte; G-CSF; Macrophage; Streptococcus pneumoniae endopeptidase O (PepO); Trained immunity
    DOI:  https://doi.org/10.1016/j.clim.2024.110226
  4. Pathogens. 2024 Mar 24. pii: 276. [Epub ahead of print]13(4):
    Staphylococcus aureus Infections and Human Intestinal Microbiota.
    Aotong Liu, Shari Garrett, Wanqing Hong, Jilei Zhang.
      Staphylococcus aureus (S. aureus) is a common pathogen that can cause many human diseases, such as skin infection, food poisoning, endocarditis, and sepsis. These diseases can be minor infections or life-threatening, requiring complex medical management resulting in substantial healthcare costs. Meanwhile, as the critically ignored "organ," the intestinal microbiome greatly impacts physiological health, not only in gastrointestinal diseases but also in disorders beyond the gut. However, the correlation between S. aureus infection and intestinal microbial homeostasis is largely unknown. Here, we summarized the recent progress in understanding S. aureus infections and their interactions with the microbiome in the intestine. These summarizations will help us understand the mechanisms behind these infections and crosstalk and the challenges we are facing now, which could contribute to preventing S. aureus infections, effective treatment investigation, and vaccine development.
    Keywords:  Staphylococcus aureus; bacterial translocation; dysbiosis; gut microbiome; microbial homeostasis
    DOI:  https://doi.org/10.3390/pathogens13040276
  5. Microorganisms. 2024 Apr 03. pii: 732. [Epub ahead of print]12(4):
    How Does Airway Surface Liquid Composition Vary in Different Pulmonary Diseases, and How Can We Use This Knowledge to Model Microbial Infections?
    Dean Walsh, Jennifer Bevan, Freya Harrison.
      Growth environment greatly alters many facets of pathogen physiology, including pathogenesis and antimicrobial tolerance. The importance of host-mimicking environments for attaining an accurate picture of pathogen behaviour is widely recognised. Whilst this recognition has translated into the extensive development of artificial cystic fibrosis (CF) sputum medium, attempts to mimic the growth environment in other respiratory disease states have been completely neglected. The composition of the airway surface liquid (ASL) in different pulmonary diseases is far less well characterised than CF sputum, making it very difficult for researchers to model these infection environments. In this review, we discuss the components of human ASL, how different lung pathologies affect ASL composition, and how different pathogens interact with these components. This will provide researchers interested in mimicking different respiratory environments with the information necessary to design a host-mimicking medium, allowing for better understanding of how to treat pathogens causing infection in these environments.
    Keywords:  airway surface liquid; asthma; biofilm cystic fibrosis; host-mimicking media; respiratory infection; sputum; ventilator-associated pneumonia
    DOI:  https://doi.org/10.3390/microorganisms12040732
  6. Nat Immunol. 2024 Apr 26.
    Apolipoprotein E controls Dectin-1-dependent development of monocyte-derived alveolar macrophages upon pulmonary β-glucan-induced inflammatory adaptation.
    H Theobald, D A Bejarano, N Katzmarski, J Haub, J Schulte-Schrepping, J Yu, K Bassler, A L Ament, C Osei-Sarpong, F Piattini, L Vornholz, W T'Jonck, A H Györfi, H Hayer, X Yu, S Sheoran, A Al Jawazneh, S Chakarov, K Haendler, G D Brown, D L Williams, L Bosurgi, J H W Distler, F Ginhoux, J Ruland, M D Beyer, M Greter, C C Bain, A I Vazquez-Armendariz, M Kopf, J L Schultze, A Schlitzer.
      The lung is constantly exposed to the outside world and optimal adaptation of immune responses is crucial for efficient pathogen clearance. However, mechanisms that lead to lung-associated macrophages' functional and developmental adaptation remain elusive. To reveal such mechanisms, we developed a reductionist model of environmental intranasal β-glucan exposure, allowing for the detailed interrogation of molecular mechanisms of pulmonary macrophage adaptation. Employing single-cell transcriptomics, high-dimensional imaging and flow cytometric characterization paired with in vivo and ex vivo challenge models, we reveal that pulmonary low-grade inflammation results in the development of apolipoprotein E (ApoE)-dependent monocyte-derived alveolar macrophages (ApoE+CD11b+ AMs). ApoE+CD11b+ AMs expressed high levels of CD11b, ApoE, Gpnmb and Ccl6, were glycolytic, highly phagocytic and produced large amounts of interleukin-6 upon restimulation. Functional differences were cell intrinsic, and myeloid cell-specific ApoE ablation inhibited Ly6c+ monocyte to ApoE+CD11b+ AM differentiation dependent on macrophage colony-stimulating factor secretion, promoting ApoE+CD11b+ AM cell death and thus impeding ApoE+CD11b+ AM maintenance. In vivo, β-glucan-elicited ApoE+CD11b+ AMs limited the bacterial burden of Legionella pneumophilia after infection and improved the disease outcome in vivo and ex vivo in a murine lung fibrosis model. Collectively these data identify ApoE+CD11b+ AMs generated upon environmental cues, under the control of ApoE signaling, as an essential determinant for lung adaptation enhancing tissue resilience.
    DOI:  https://doi.org/10.1038/s41590-024-01830-z
  7. Int J Mol Sci. 2024 Apr 10. pii: 4178. [Epub ahead of print]25(8):
    Activation of the RIG-I/MAVS Signaling Pathway during Human Adenovirus Type 3 Infection Impairs the Pro-Inflammatory Response Induced by Secondary Infection with Staphylococcus aureus.
    Jiehan Chen, Qiaowen Wang, Biying Zhong, Huiying Zheng, Dingjun Wang, Xiao Huang, Li Liu, Tiantian Liu.
      The exacerbation of pneumonia in children with human adenovirus type 3 (HAdV-3E) is secondary to a Staphylococcus aureus (S. aureus) infection. The influence of host-pathogen interactions on disease progression remains unclear. It is important to note that S. aureus infections following an HAdV-3E infection are frequently observed in clinical settings, yet the underlying susceptibility mechanisms are not fully understood. This study utilized an A549 cell model to investigate secondary infection with S. aureus following an HAdV-3E infection. The findings suggest that HAdV-3E exacerbates the S. aureus infection by intensifying lung epithelial cell damage. The results highlight the role of HAdV-3E in enhancing the interferon signaling pathway through RIG-I (DDX58), resulting in the increased expression of interferon-stimulating factors like MX1, RSAD2, and USP18. The increase in interferon-stimulating factors inhibits the NF-κB and MAPK/P38 pro-inflammatory signaling pathways. These findings reveal new mechanisms of action for HAdV-3E and S. aureus in secondary infections, enhancing our comprehension of pathogenesis.
    Keywords:  Staphylococcus aureus; adenovirus type 3; coinfection
    DOI:  https://doi.org/10.3390/ijms25084178
  8. Front Immunol. 2024 ;15 1352946
    Macrophage polarization: an important role in inflammatory diseases.
    Min Luo, Fukun Zhao, Huan Cheng, Mu Su, Yuanmin Wang.
      Macrophages are crucial cells in the human body's innate immunity and are engaged in a variety of non-inflammatory reactions. Macrophages can develop into two kinds when stimulated by distinct internal environments: pro-inflammatory M1-like macrophages and anti-inflammatory M2-type macrophages. During inflammation, the two kinds of macrophages are activated alternatively, and maintaining a reasonably steady ratio is critical for maintaining homeostasis in vivo. M1 macrophages can induce inflammation, but M2 macrophages suppress it. The imbalance between the two kinds of macrophages will have a significant impact on the illness process. As a result, there are an increasing number of research being conducted on relieving or curing illnesses by altering the amount of macrophages. This review summarizes the role of macrophage polarization in various inflammatory diseases, including autoimmune diseases (RA, EAE, MS, AIH, IBD, CD), allergic diseases (allergic rhinitis, allergic dermatitis, allergic asthma), atherosclerosis, obesity and type 2 diabetes, metabolic homeostasis, and the compounds or drugs that have been discovered or applied to the treatment of these diseases by targeting macrophage polarization.
    Keywords:  M1; M2; inflammatory disease; macrophage; mechanism; therapeutic application
    DOI:  https://doi.org/10.3389/fimmu.2024.1352946
  9. PLoS Biol. 2024 Apr;22(4): e3002566
    Lytic bacteriophages induce the secretion of antiviral and proinflammatory cytokines from human respiratory epithelial cells.
    Paula F Zamora, Thomas G Reidy, Catherine R Armbruster, Ming Sun, Daria Van Tyne, Paul E Turner, Jonathan L Koff, Jennifer M Bomberger.
      Phage therapy is a therapeutic approach to treat multidrug-resistant (MDR) infections that employs lytic bacteriophages (phages) to eliminate bacteria. Despite the abundant evidence for its success as an antimicrobial in Eastern Europe, there is scarce data regarding its effects on the human host. Here, we aimed to understand how lytic phages interact with cells of the airway epithelium, the tissue site that is colonized by bacterial biofilms in numerous chronic respiratory disorders. Using a panel of Pseudomonas aeruginosa phages and human airway epithelial cells (AECs) derived from a person with cystic fibrosis (CF), we determined that interactions between phages and epithelial cells depend on specific phage properties as well as physiochemical features of the microenvironment. Although poor at internalizing phages, the airway epithelium responds to phage exposure by changing its transcriptional profile and secreting antiviral and proinflammatory cytokines that correlate with specific phage families. Overall, our findings indicate that mammalian responses to phages are heterogenous and could potentially alter the way that respiratory local defenses aid in bacterial clearance during phage therapy. Thus, besides phage receptor specificity in a particular bacterial isolate, the criteria to select lytic phages for therapy should be expanded to include mammalian cell responses.
    DOI:  https://doi.org/10.1371/journal.pbio.3002566
  10. BMC Microbiol. 2024 Apr 20. 24(1): 130
    Establishment of an in vitro model of monocyte-like THP-1 cells for trained immunity induced by bacillus Calmette-Guérin.
    Jin-Chuan Xu, Kang Wu, Rui-Qing Ma, Jian-Hui Li, Jie Tao, Zhidong Hu, Xiao-Yong Fan.
       BACKGROUND: Mycobacteria bloodstream infections are common in immunocompromised people and usually have disastrous consequences. As the primary phagocytes in the bloodstream, monocytes and neutrophils play critical roles in the fight against bloodstream mycobacteria infections. In contrast to macrophages, the responses of monocytes infected with the mycobacteria have been less investigated.
    RESULTS: In this study, we first established a protocol for infection of non-adherent monocyte-like THP-1 cells (i.e. without the differentiation induced by phorbol 12-myristate 13-acetate (PMA) by bacillus Calmette-Guérin (BCG). Via the protocol, we were then capable of exploring the global transcriptomic profiles of non-adherent THP-1 cells infected with BCG, and found that NF-κB, MAPK and PI3K-Akt signaling pathways were enhanced, as well as some inflammatory chemokine/cytokine genes (e.g. CCL4, CXCL10, TNF and IL-1β) were up-regulated. Surprisingly, the Akt-HIF-mTOR signaling pathway was also activated, which induces trained immunity. In this in vitro infection model, increased cytokine responses to lipopolysaccharides (LPS) restimulation, higher cell viability, and decreased Candida albicans loads were observed.
    CONCLUSIONS: We have first characterized the transcriptomic profiles of BCG-infected non-adherent THP-1 cells, and first developed a trained immunity in vitro model of the cells.
    Keywords:  Bacillus Calmette-Guérin (BCG); Monocyte; THP-1; Trained immunity
    DOI:  https://doi.org/10.1186/s12866-024-03191-x
  11. Respir Res. 2024 Apr 20. 25(1): 174
    PPARγ attenuates cellular senescence of alveolar macrophages in asthma-COPD overlap.
    Rongjun Wan, Prakhyath Srikaram, Shaobing Xie, Qiong Chen, Chengping Hu, Mei Wan, Yuanyuan Li, Peisong Gao.
       BACKGROUND: Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) represents a complex condition characterized by shared clinical and pathophysiological features of asthma and COPD in older individuals. However, the pathophysiology of ACO remains unexplored. We aimed to identify the major inflammatory cells in ACO, examine senescence within these cells, and elucidate the genes responsible for regulating senescence.
    METHODS: Bioinformatic analyses were performed to investigate major cell types and cellular senescence signatures in a public single-cell RNA sequencing (scRNA-Seq) dataset derived from the lung tissues of patients with ACO. Similar analyses were carried out in an independent cohort study Immune Mechanisms Severe Asthma (IMSA), which included bulk RNA-Seq and CyTOF data from bronchoalveolar lavage fluid (BALF) samples.
    RESULTS: The analysis of the scRNA-Seq data revealed that monocytes/ macrophages were the predominant cell type in the lung tissues of ACO patients, constituting more than 50% of the cells analyzed. Lung monocytes/macrophages from patients with ACO exhibited a lower prevalence of senescence as defined by lower enrichment scores of SenMayo and expression levels of cellular senescence markers. Intriguingly, analysis of the IMSA dataset showed similar results in patients with severe asthma. They also exhibited a lower prevalence of senescence, particularly in airway CD206 + macrophages, along with increased cytokine expression (e.g., IL-4, IL-13, and IL-22). Further exploration identified alveolar macrophages as a major subtype of monocytes/macrophages driving cellular senescence in ACO. Differentially expressed genes related to oxidation-reduction, cytokines, and growth factors were implicated in regulating senescence in alveolar macrophages. PPARγ (Peroxisome Proliferator-Activated Receptor Gamma) emerged as one of the predominant regulators modulating the senescent signature of alveolar macrophages in ACO.
    CONCLUSION: The findings suggest that senescence in macrophages, particularly alveolar macrophages, plays a crucial role in the pathophysiology of ACO. Furthermore, PPARγ may represent a potential therapeutic target for interventions aimed at modulating senescence-associated processes in ACO.Key words ACO, Asthma, COPD, Macrophages, Senescence, PPARγ.
    Keywords:  ACO; Asthma; COPD; Macrophages; PPARγ; Senescence
    DOI:  https://doi.org/10.1186/s12931-024-02790-6
  12. mBio. 2024 Apr 23. e0345123
    Mucus polymer concentration and in vivo adaptation converge to define the antibiotic response of Pseudomonas aeruginosa during chronic lung infection.
    Matthew A Greenwald, Suzanne L Meinig, Lucas M Plott, Cristian Roca, Matthew G Higgs, Nicholas P Vitko, Matthew R Markovetz, Kaitlyn R Rouillard, Jerome Carpenter, Mehmet Kesimer, David B Hill, Jonathan C Schisler, Matthew C Wolfgang.
      The airway milieu of individuals with muco-obstructive airway diseases (MADs) is defined by the accumulation of dehydrated mucus due to hyperabsorption of airway surface liquid and defective mucociliary clearance. Pathological mucus becomes progressively more viscous with age and disease severity due to the concentration and overproduction of mucin and accumulation of host-derived extracellular DNA (eDNA). Respiratory mucus of MADs provides a niche for recurrent and persistent colonization by respiratory pathogens, including Pseudomonas aeruginosa, which is responsible for the majority of morbidity and mortality in MADs. Despite high concentration inhaled antibiotic therapies and the absence of antibiotic resistance, antipseudomonal treatment failure in MADs remains a significant clinical challenge. Understanding the drivers of antibiotic tolerance is essential for developing more effective treatments that eradicate persistent infections. The complex and dynamic environment of diseased airways makes it difficult to model antibiotic efficacy in vitro. We aimed to understand how mucin and eDNA concentrations, the two dominant polymers in respiratory mucus, alter the antibiotic tolerance of P. aeruginosa. Our results demonstrate that polymer concentration and molecular weight affect P. aeruginosa survival post antibiotic challenge. Polymer-driven antibiotic tolerance was not explicitly associated with reduced antibiotic diffusion. Lastly, we established a robust and standardized in vitro model for recapitulating the ex vivo antibiotic tolerance of P. aeruginosa observed in expectorated sputum across age, underlying MAD etiology, and disease severity, which revealed the inherent variability in intrinsic antibiotic tolerance of host-evolved P. aeruginosa populations.
    IMPORTANCE: Antibiotic treatment failure in Pseudomonas aeruginosa chronic lung infections is associated with increased morbidity and mortality, illustrating the clinical challenge of bacterial infection control. Understanding the underlying infection environment, as well as the host and bacterial factors driving antibiotic tolerance and the ability to accurately recapitulate these factors in vitro, is crucial for improving antibiotic treatment outcomes. Here, we demonstrate that increasing concentration and molecular weight of mucin and host eDNA drive increased antibiotic tolerance to tobramycin. Through systematic testing and modeling, we identified a biologically relevant in vitro condition that recapitulates antibiotic tolerance observed in ex vivo treated sputum. Ultimately, this study revealed a dominant effect of in vivo evolved bacterial populations in defining inter-subject ex vivo antibiotic tolerance and establishes a robust and translatable in vitro model for therapeutic development.
    Keywords:  P. aeruginosa; antibiotic efficacy; muco-obstructive airway disease; sputum; tobramycin
    DOI:  https://doi.org/10.1128/mbio.03451-23
  13. Naunyn Schmiedebergs Arch Pharmacol. 2024 Apr 23.
    Ischemia does not provoke the full immune training repertoire in human cardiac fibroblasts.
    Constantin Mann, Carolin van Alst, Simone Gorressen, Rachel Nega, Dobromir Dobrev, Maria Grandoch, Anke C Fender.
      Trained immunity of monocytes, endothelial, and smooth muscle cells augments the cytokine response to secondary stimuli. Immune training is characterized by stabilization of hypoxia-inducible factor (HIF)-1α, mTOR activation, and aerobic glycolysis. Cardiac fibroblast (CF)-myofibroblast transition upon myocardial ischemia/reperfusion (I/R) features epigenetic and metabolic adaptations reminiscent of trained immunity. We assessed the impact of I/R on characteristics of immune training in human CF and mouse myocardium. I/R was simulated in vitro with transient metabolic inhibition. CF primed with simulated I/R or control buffer were 5 days later re-stimulated with Pam3CSK for 24 h. Mice underwent transient left anterior descending artery occlusion or sham operation with reperfusion for up to 5 days. HIF-regulated metabolic targets and cytokines were assessed by qPCR, immunoblot, and ELISA and glucose consumption, lactate release, and lactate dehydrogenase (LDH) by chromogenic assay. Simulated I/R increased HIF-1α stabilization, mTOR phosphorylation, glucose consumption, lactate production, and transcription of PFKB3 and F2RL3, a HIF-regulated target gene, in human CF. PGK1 and LDH mRNAs were suppressed. Intracellular LDH transiently increased after simulated I/R, and extracellular LDH showed sustained elevation. I/R priming increased abundance of pro-caspase-1, auto-cleaved active caspase-1, and the expression and secretion of interleukin (IL)-1β, but did not augment Pam3CSK-stimulated cytokine transcription or secretion. Myocardial I/R in vivo increased abundance of HIF-1 and the precursor and cleaved forms of caspase-1, caspase-11, and caspase-8, but not of LDH-A or phospho-mTOR. I/R partially reproduces features of immune training in human CF, specifically HIF-1α stabilization, aerobic glycolysis, mTOR phosphorylation, and PFKB3 transcription. I/R does not augment PGK1 or LDH expression or the cytokine response to Pam3CSK. Regulation of PAR4 and inflammasome caspases likely occurs independently of an immune training repertoire.
    Keywords:  Cardiac fibroblasts; Glycolysis; Inflammasome; Ischemia; Myocardial; Trained immunity
    DOI:  https://doi.org/10.1007/s00210-024-03107-6
  14. Cell Immunol. 2024 Apr 20. pii: S0008-8749(24)00028-5. [Epub ahead of print]399-400 104825
    Macrophage niche imprinting as a determinant of macrophage identity and function.
    Malgorzata Kloc, Marta Halasa, Rafik M Ghobrial.
      Macrophage niches are the anatomical locations within organs or tissues consisting of various cells, intercellular and extracellular matrix, transcription factors, and signaling molecules that interact to influence macrophage self-maintenance, phenotype, and behavior. The niche, besides physically supporting macrophages, imposes a tissue- and organ-specific identity on the residing and infiltrating monocytes and macrophages. In this review, we give examples of macrophage niches and the modes of communication between macrophages and surrounding cells. We also describe how macrophages, acting against their immune defensive nature, can create a hospitable niche for pathogens and cancer cells.
    Keywords:  Embryonic precursors; Macrophage; Macrophage life span; Monocyte-derived macrophages; Niche; Self-maintenance; Tissue resident macrophages
    DOI:  https://doi.org/10.1016/j.cellimm.2024.104825
  15. Vaccines (Basel). 2024 Apr 09. pii: 396. [Epub ahead of print]12(4):
    Vaccines Induce Homeostatic Immunity, Generating Several Secondary Benefits.
    Arun B Arunachalam.
      The optimal immune response eliminates invading pathogens, restoring immune equilibrium without inflicting undue harm to the host. However, when a cascade of immunological reactions is triggered, the immune response can sometimes go into overdrive, potentially leading to harmful long-term effects or even death. The immune system is triggered mostly by infections, allergens, or medical interventions such as vaccination. This review examines how these immune triggers differ and why certain infections may dysregulate immune homeostasis, leading to inflammatory or allergic pathology and exacerbation of pre-existing conditions. However, many vaccines generate an optimal immune response and protect against the consequences of pathogen-induced immunological aggressiveness, and from a small number of unrelated pathogens and autoimmune diseases. Here, we propose an "immuno-wave" model describing a vaccine-induced "Goldilocks immunity", which leaves fine imprints of both pro-inflammatory and anti-inflammatory milieus, derived from both the innate and the adaptive arms of the immune system, in the body. The resulting balanced, 'quiet alert' state of the immune system may provide a jump-start in the defense against pathogens and any associated pathological inflammatory or allergic responses, allowing vaccines to go above and beyond their call of duty. In closing, we recommend formally investigating and reaping many of the secondary benefits of vaccines with appropriate clinical studies.
    Keywords:  adaptive immunity; cytokine storm; homeostasis; immuno-wave model; infections; innate immunity; para-specific effect; trained immunity; vaccine
    DOI:  https://doi.org/10.3390/vaccines12040396
  16. Int J Mol Sci. 2024 Apr 12. pii: 4265. [Epub ahead of print]25(8):
    Neutrophil Elastase Degrades Histone Deacetylases and Sirtuin 1 in Primary Human Monocyte Derived Macrophages.
    Shuo Zheng, Gamze B Bulut, Apparao B Kummarapurugu, Jonathan Ma, Judith A Voynow.
      Neutrophil elastase (NE) is taken up by macrophages, retains intracellular protease activity, and induces a pro-inflammatory phenotype. However, the mechanism of NE-induced pro-inflammatory polarization of macrophages is not well understood. We hypothesized that intracellular NE degrades histone deacetylases (HDAC) and Sirtuins, disrupting the balance of lysine acetylation and deacetylation and resulting in nuclear to cytoplasmic translocation of a major alarmin, High Mobility Group Box 1 (HMGB1), a pro-inflammatory response in macrophages. Human blood monocytes were obtained from healthy donors or from subjects with cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD). Monocytes were differentiated into blood monocyte derived macrophages (BMDMs) in vitro. Human BMDMs were exposed to NE or control vehicle, and the abundance of HDACs and Sirtuins was determined by Western blotting of total cell lysates or nuclear extracts or determined by ELISA. HDAC, Sirtuin, and Histone acetyltransferase (HAT) activities were measured. NE degraded most HDACs and Sirtuin (Sirt)1, resulting in decreased HDAC and sirtuin activities, with minimal change in HAT activity. We then evaluated whether the NE-induced loss of Sirt activity or loss of HDAC activities would alter the cellular localization of HMGB1. NE treatment or treatment with Trichostatin A (TSA), a global HDAC inhibitor, both increased HMGB1 translocation from the nucleus to the cytoplasm, consistent with HMGB1 activation. NE significantly degraded Class I and II HDAC family members and Sirt 1, which shifted BMDMs to a pro-inflammatory phenotype.
    Keywords:  COPD; HDACs; HMGB1; Sirtuin; cystic fibrosis; macrophage; neutrophil elastase
    DOI:  https://doi.org/10.3390/ijms25084265
  17. J Immunol. 2024 Apr 22. pii: ji2300646. [Epub ahead of print]
    Single-Cell Analysis Uncovers Striking Cellular Heterogeneity of Lung-Infiltrating Regulatory T Cells during Eosinophilic versus Neutrophilic Allergic Airway Inflammation.
    Supinya Iamsawat, Rongzhen Yu, Sohee Kim, Nina Dvorina, Kevin Qiu, Jaehyuk Choi, William M Baldwin, Booki Min.
      Allergic airway inflammation results from uncontrolled immune responses to environmental Ags. Although it is well established that allergic immune responses exhibit a high degree of diversity, driven by primary effector cell types such as eosinophils, neutrophils, or CD4 T cells with distinct effector signatures, the mechanisms responsible for such pathogenesis remain elusive. Foxp3+ regulatory T cells (Tregs) are essential immune regulators during chronic inflammation, including allergic airway inflammation. Emerging evidence suggests that Tregs infiltrating inflamed tissues exhibit distinct phenotypes dependent on the specific tissue sites and can display heterogeneity and tissue residency. Whether diverse allergic airway inflammatory responses influence infiltrating Treg heterogeneity or Treg lung residency has not been explored. We employed an unbiased single-cell RNA sequencing approach to investigate lung-infiltrating Tregs in models of eosinophilic and neutrophilic airway inflammation. We found that lung-infiltrating Tregs are highly heterogeneous, and that Tregs displaying lung-resident phenotypes are significantly different depending on the types of inflammation. Treg expression of ST2, a receptor for alarmin IL-33, was predominantly associated with eosinophilic inflammation and tissue residency. Nevertheless, Treg-specific ST2 deficiency did not affect the development of eosinophilic allergic inflammation or the generation of lung-resident Tregs. These results uncover a stark heterogeneity among Tregs infiltrating the lungs during allergic airway inflammation. The results indicate that varying types of inflammation may give rise to phenotypically distinct lung-resident Tregs, underscoring a (to our knowledge) novel mechanism by which inflammatory cues may shape the composition of infiltrating Tregs, allowing them to regulate inflammatory responses through tissue-adapted mechanisms.
    DOI:  https://doi.org/10.4049/jimmunol.2300646
  18. Microbiol Res. 2024 Apr 17. pii: S0944-5013(24)00129-0. [Epub ahead of print]284 127728
    Induction of ferroptosis: A new strategy for the control of bacterial infections.
    Rongxian Guo, Xin Fang, Ke Shang, Jiachen Wen, Ke Ding.
      The continued rise of drug-resistant bacterial infections heightens a threat of a pandemic of antimicrobial resistance to the global health. The urgency of infection control against antimicrobial-resistant bacteria is evident. Ferroptosis, a newly defined form of iron-dependent cell death characterized by lipid peroxidation, has garnered substantial interest since this programmed cell death was associated with pathophysiological processes of many diseases. Exploring whether ferroptosis could be utilized in infectious diseases holds significant importance for discovering novel antimicrobial approaches. Recent years have witnessed significant progress with respect to elucidating the mechanisms that govern ferroptosis induction and its roles in bacterial pathogenesis and host-pathogen interactions. In this review, we discuss the mechanisms of targeting ferroptosis and/or iron homeostasis for the control of antimicrobial-resistant bacterial infections. These implications may inform and enable effective therapeutic strategies against pathogen infection and provide novel insights into the potential applications of ferroptosis to address the global bacterial resistance crisis.
    Keywords:  Antimicrobial resistance; Ferroptosis; Host–pathogen interactions; Intracellular pathogen
    DOI:  https://doi.org/10.1016/j.micres.2024.127728
  19. FASEB J. 2024 Apr 30. 38(8): e23612
    Repair and regeneration of the alveolar epithelium in lung injury.
    Yaxuan Wang, Lan Wang, Shuaichen Ma, Lianhui Cheng, Guoying Yu.
      Considerable progress has been made in understanding the function of alveolar epithelial cells in a quiescent state and regeneration mechanism after lung injury. Lung injury occurs commonly from severe viral and bacterial infections, inhalation lung injury, and indirect injury sepsis. A series of pathological mechanisms caused by excessive injury, such as apoptosis, autophagy, senescence, and ferroptosis, have been studied. Recovery from lung injury requires the integrity of the alveolar epithelial cell barrier and the realization of gas exchange function. Regeneration mechanisms include the participation of epithelial progenitor cells and various niche cells involving several signaling pathways and proteins. While alveoli are damaged, alveolar type II (AT2) cells proliferate and differentiate into alveolar type I (AT1) cells to repair the damaged alveolar epithelial layer. Alveolar epithelial cells are surrounded by various cells, such as fibroblasts, endothelial cells, and various immune cells, which affect the proliferation and differentiation of AT2 cells through paracrine during alveolar regeneration. Besides, airway epithelial cells also contribute to the repair and regeneration process of alveolar epithelium. In this review, we mainly discuss the participation of epithelial progenitor cells and various niche cells involving several signaling pathways and transcription factors.
    Keywords:  alveolar regeneration; epithelial function; lung injury; niche; progenitor cells
    DOI:  https://doi.org/10.1096/fj.202400088R
  20. Front Immunol. 2024 ;15 1365718
    Exploring the role of CITED transcriptional regulators in the control of macrophage polarization.
    Derek A Wiggins, Jack N Maxwell, David E Nelson.
      Macrophages are tissue resident innate phagocytic cells that take on contrasting phenotypes, or polarization states, in response to the changing combination of microbial and cytokine signals at sites of infection. During the opening stages of an infection, macrophages adopt the proinflammatory, highly antimicrobial M1 state, later shifting to an anti-inflammatory, pro-tissue repair M2 state as the infection resolves. The changes in gene expression underlying these transitions are primarily governed by nuclear factor kappaB (NF-κB), Janus kinase (JAK)/signal transducer and activation of transcription (STAT), and hypoxia-inducible factor 1 (HIF1) transcription factors, the activity of which must be carefully controlled to ensure an effective yet spatially and temporally restricted inflammatory response. While much of this control is provided by pathway-specific feedback loops, recent work has shown that the transcriptional co-regulators of the CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxy-terminal domain (CITED) family serve as common controllers for these pathways. In this review, we describe how CITED proteins regulate polarization-associated gene expression changes by controlling the ability of transcription factors to form chromatin complexes with the histone acetyltransferase, CBP/p300. We will also cover how differences in the interactions between CITED1 and 2 with CBP/p300 drive their contrasting effects on pro-inflammatory gene expression.
    Keywords:  CBP/p300; CITED1; CITED2; NF-κB; STAT1; inflammation; innate immunity; macrophage
    DOI:  https://doi.org/10.3389/fimmu.2024.1365718
  21. Sci Rep. 2024 04 23. 14(1): 9287
    Bacterial diversity dominates variable macrophage responses of tuberculosis patients in Tanzania.
    Hellen Hiza, Michaela Zwyer, Jerry Hella, Ainhoa Arbués, Mohamed Sasamalo, Sonia Borrell, Zhi Ming Xu, Amanda Ross, Daniela Brites, Jacques Fellay, Klaus Reither, Sébastien Gagneux, Damien Portevin.
      The Mycobacterium tuberculosis complex (MTBC) comprises nine human-adapted lineages that differ in their geographical distribution. Local adaptation of specific MTBC genotypes to the respective human host population has been invoked in this context. We aimed to assess if bacterial genetics governs MTBC pathogenesis or if local co-adaptation translates into differential susceptibility of human macrophages to infection by different MTBC genotypes. We generated macrophages from cryopreserved blood mononuclear cells of Tanzanian tuberculosis patients, from which the infecting MTBC strains had previously been phylogenetically characterized. We infected these macrophages ex vivo with a phylogenetically similar MTBC strain ("matched infection") or with strains representative of other MTBC lineages ("mismatched infection"). We found that L1 infections resulted in a significantly lower bacterial burden and that the intra-cellular replication rate of L2 strains was significantly higher compared the other MTBC lineages, irrespective of the MTBC lineage originally infecting the patients. Moreover, L4-infected macrophages released significantly greater amounts of TNF-α, IL-6, IL-10, MIP-1β, and IL-1β compared to macrophages infected by all other strains. While our results revealed no measurable effect of local adaptation, they further highlight the strong impact of MTBC phylogenetic diversity on the variable outcome of the host-pathogen interaction in human tuberculosis.
    Keywords:  Cytokine; Infection; Macrophage; Mycobacterium tuberculosis complex; Patient; Tanzania
    DOI:  https://doi.org/10.1038/s41598-024-60001-0
  22. Microorganisms. 2024 Apr 14. pii: 794. [Epub ahead of print]12(4):
    Molecular Mechanisms of Lacticaseibacillus rhamnosus, LGG® Probiotic Function.
    Thomas Leser, Adam Baker.
      To advance probiotic research, a comprehensive understanding of bacterial interactions with human physiology at the molecular and cellular levels is fundamental. Lacticaseibacillus rhamnosus LGG® is a bacterial strain that has long been recognized for its beneficial effects on human health. Probiotic effector molecules derived from LGG®, including secreted proteins, surface-anchored proteins, polysaccharides, and lipoteichoic acids, which interact with host physiological processes have been identified. In vitro and animal studies have revealed that specific LGG® effector molecules stimulate epithelial cell survival, preserve intestinal barrier integrity, reduce oxidative stress, mitigate excessive mucosal inflammation, enhance IgA secretion, and provide long-term protection through epigenetic imprinting. Pili on the cell surface of LGG® promote adhesion to the intestinal mucosa and ensure close contact to host cells. Extracellular vesicles produced by LGG® recapitulate many of these effects through their cargo of effector molecules. Collectively, the effector molecules of LGG® exert a significant influence on both the gut mucosa and immune system, which promotes intestinal homeostasis and immune tolerance.
    Keywords:  LGG®; Lacticaseibacillus rhamnosus; effector molecules; homeostasis; pili; proteins; tolerance
    DOI:  https://doi.org/10.3390/microorganisms12040794
  23. Cytometry A. 2024 Apr 23.
    A 30-color spectral flow cytometry panel for comprehensive analysis of immune cell composition and macrophage subsets in mouse metabolic organs.
    Joost M Lambooij, Tamar Tak, Arnaud Zaldumbide, Bruno Guigas.
      Obesity-induced chronic low-grade inflammation, also known as metaflammation, results from alterations of the immune response in metabolic organs and contributes to the development of fatty liver diseases and type 2 diabetes. The diversity of tissue-resident leukocytes involved in these metabolic dysfunctions warrants an in-depth immunophenotyping in order to elucidate disease etiology. Here, we present a 30-color, full spectrum flow cytometry panel, designed to (i) identify the major innate and adaptive immune cell subsets in murine liver and white adipose tissues and (ii) discriminate various tissue-specific myeloid subsets known to contribute to the development of metabolic dysfunctions. This panel notably allows for distinguishing embryonically-derived liver-resident Kupffer cells from newly recruited monocyte-derived macrophages and KCs. Furthermore, several adipose tissue macrophage (ATM) subsets, including perivascular macrophages, lipid-associated macrophages, and pro-inflammatory CD11c+ ATMs, can also be identified. Finally, the panel includes cell-surface markers that have been associated with metabolic activation of different macrophage and dendritic cell subsets. Altogether, our spectral flow cytometry panel allows for an extensive immunophenotyping of murine metabolic tissues, with a particular focus on metabolically-relevant myeloid cell subsets, and can easily be adjusted to include various new markers if needed.
    Keywords:  NAFLD; adipose tissue; immunometabolism; innate and adaptive immunity; liver; macrophages; obesity; spectral flow cytometry
    DOI:  https://doi.org/10.1002/cyto.a.24845
  24. Nutrients. 2024 Apr 19. pii: 1212. [Epub ahead of print]16(8):
    Novel Fermentates Can Enhance Key Immune Responses Associated with Viral Immunity.
    Dearbhla Finnegan, Monica A Mechoud, Jamie A FitzGerald, Tom Beresford, Harsh Mathur, Paul D Cotter, Christine Loscher.
      Fermented foods have long been known to have immunomodulatory capabilities, and fermentates derived from the lactic acid bacteria of dairy products can modulate the immune system. We have used skimmed milk powder to generate novel fermentates using Lb. helveticus strains SC234 and SC232 and we demonstrate here that these fermentates can enhance key immune mechanisms that are critical to the immune response to viruses. We show that our novel fermentates, SC234 and SC232, can positively impact on cytokine and chemokine secretion, nitric oxide (NO) production, cell surface marker expression, and phagocytosis in macrophage models. We demonstrate that the fermentates SC234 and SC232 increase the secretion of cytokines IL-1β, IL-6, TNF-α, IL-27, and IL-10; promote an M1 pro-inflammatory phenotype for viral immunity via NO induction; decrease chemokine expression of Monocyte Chemoattractant Protein (MCP); increase cell surface marker expression; and enhance phagocytosis in comparison to their starting material. These data suggest that these novel fermentates have potential as novel functional food ingredients for the treatment, management, and control of viral infection.
    Keywords:  fermentates; functional food; immune boosting; immunomodulation; macrophage; viral immunity
    DOI:  https://doi.org/10.3390/nu16081212
  25. PeerJ. 2024 ;12 e17106
    S100A8/9 modulates perturbation and glycolysis of macrophages in allergic asthma mice.
    Xiaoyi Ji, Chunhua Nie, Yuan Yao, Yu Ma, Huafei Huang, Chuangli Hao.
       Background: Allergic asthma is the most prevalent asthma phenotype and is associated with the disorders of immune cells and glycolysis. Macrophages are the most common type of immune cells in the lungs. Calprotectin (S100A8 and S100A9) are two pro-inflammatory molecules that target the Toll-like receptor 4 (TLR4) and are substantially increased in the serum of patients with severe asthma. This study aimed to determine the effects of S100A8/A9 on macrophage polarization and glycolysis associated with allergic asthma.
    Methods: To better understand the roles of S100A8 and S100A9 in the pathogenesis of allergic asthma, we used ovalbumin (OVA)-induced MH-S cells, and OVA-sensitized and challenged mouse models (wild-type male BALB/c mice). Enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, flow cytometry, hematoxylin-eosin staining, and western blotting were performed. The glycolysis inhibitor 3-bromopyruvate (3-BP) was used to observe changes in glycolysis in mice.
    Results: We found knockdown of S100A8 or S100A9 in OVA-induced MH-S cells inhibited inflammatory cytokines, macrophage polarization biomarker expression, and pyroptosis cell proportion, but increased anti-inflammatory cytokine interleukin (IL)-10 mRNA; also, glycolysis was inhibited, as evidenced by decreased lactate and key enzyme expression; especially, knockdown of S100A8 or S100A9 inhibited the activity of TLR4/myeloid differentiation primary response gene 88 (MyD88)/Nuclear factor kappa-B (NF-κB) signaling pathway. Intervention with lipopolysaccharides (LPS) abolished the beneficial effects of S100A8 and S100A9 knockdown. The observation of OVA-sensitized and challenged mice showed that S100A8 or S100A9 knockdown promoted respiratory function, improved lung injury, and inhibited inflammation; knockdown of S100A8 or S100A9 also suppressed macrophage polarization, glycolysis levels, and activation of the TLR4/MyD88/NF-κB signaling pathway in the lung. Conversely, S100A9 overexpression exacerbated lung injury and inflammation, promoting macrophage polarization and glycolysis, which were antagonized by the glycolysis inhibitor 3-BP.
    Conclusion: S100A8 and S100A9 play critical roles in allergic asthma pathogenesis by promoting macrophage perturbation and glycolysis through the TLR4/MyD88/NF-κB signaling pathway. Inhibition of S100A8 and S100A9 may be a potential therapeutic strategy for allergic asthma.
    Keywords:  Allergic asthma; Glycolysis; Macrophages perturbation; S100A8/9; TLR4/MyD88/NF-κB
    DOI:  https://doi.org/10.7717/peerj.17106
  26. Cytokine. 2024 Apr 25. pii: S1043-4666(24)00122-4. [Epub ahead of print]179 156619
    IL-23 regulation of myeloid cell biology during inflammation.
    Kevin M-C Lee, Tanya Lupancu, Leon Chang, Carl L Manthey, Martha Zeeman, Anne M Fourie, John A Hamilton.
      Interleukin (IL)-23 is implicated in the pathogenesis of several inflammatory diseases and is usually linked with helper T cell (Th17) biology. However, there is some data linking IL-23 with innate immune biology in such diseases. We therefore examined the effects of IL-23p19 genetic deletion and/or neutralization on in vitro macrophage activation and in an innate immune-driven peritonitis model. We report that endogenous IL-23 was required for maximal macrophage activation by zymosan as determined by pro-inflammatory cytokine production, including a dramatic upregulation of granulocyte-colony stimulating factor (G-CSF). Furthermore, both IL-23p19 genetic deletion and neutralization in zymosan-induced peritonitis (ZIP) led to a specific reduction in the neutrophil numbers, as well as a reduction in the G-CSF levels in exudate fluids. We conclude that endogenous IL-23 can contribute significantly to macrophage activation during an inflammatory response, mostly likely via an autocrine/paracrine mechanism; of note, endogenous IL-23 can directly up-regulate macrophage G-CSF expression, which in turn is likely to contribute to the regulation of IL-23-dependent neutrophil number and function during an inflammatory response, with potential significance for IL-23 targeting particularly in neutrophil-associated inflammatory diseases.
    Keywords:  G-CSF; IL-23; Inflammation; Neutrophils
    DOI:  https://doi.org/10.1016/j.cyto.2024.156619
  27. Vaccines (Basel). 2024 Apr 12. pii: 412. [Epub ahead of print]12(4):
    Bacterium-like Particles from Corynebacterium pseudodiphtheriticum as Mucosal Adjuvant for the Development of Pneumococcal Vaccines.
    Ramiro Ortiz Moyano, Fernanda Raya Tonetti, Mariano Elean, Yoshiya Imamura, Kohtaro Fukuyama, Yoshihito Suda, Vyacheslav Melnikov, Alexander Suvorov, María Guadalupe Vizoso-Pinto, Haruki Kitazawa, Julio Villena.
      Previously, it was shown that intranasally (i.n.) administered Corynebacterium pseudodiphtheriticum 090104 (Cp) or CP-derived bacterium-like particles (BLPs) improve the immunogenicity of the pneumococcal conjugate vaccine (PCV). This work aimed to deepen the characterization of the adjuvant properties of Cp and CP-derived BLPs for their use in the development of pneumococcal vaccines. The ability of Cp and CP-derived BLPs to improve both the humoral and cellular specific immune responses induced by i.n. administered polysaccharide-based commercial pneumococcal vaccine (Pneumovax 23®) and the chimeric recombinant PSPF (PsaA-Spr1875-PspA-FliC) protein was evaluated, as well as the protection against Streptococcus pneumoniae infection in infant mice. Additionally, whether the immunization protocols, including Cp and CP-derived BLPs, together with the pneumococcal vaccines can enhance the resistance to secondary pneumococcal pneumonia induced after inflammatory lung damage mediated by the activation of Toll-like receptor 3 (TLR3) was assessed. The results showed that both Cp and CP-derived BLPs increased the immunogenicity and protection induced by two pneumococcal vaccines administered through the nasal route. Of note, the nasal priming with the PSPF T-dependent antigen co-administered with Cp or CP-derived BLPs efficiently stimulated humoral and cellular immunity and increased the resistance to primary and secondary pneumococcal infections. The CP-derived BLPs presented a stronger effect than live bacteria. Given safety concerns associated with live bacterium administration, especially in high-risk populations, such as infants, the elderly, and immunocompromised patients, BLPs emerge as an attractive mucosal adjuvant to improve the host response to pneumococcal infections and to enhance the vaccines already in the market or in development.
    Keywords:  Corynebacterium pseudodiphtheriticum; bacterium-like particles; mucosal adjuvant; pneumococcal vaccines; respiratory infection
    DOI:  https://doi.org/10.3390/vaccines12040412
  28. Adv Sci (Weinh). 2024 Apr 22. e2309725
    Lactobacillus Reuteri Vesicles Regulate Mitochondrial Function of Macrophages to Promote Mucosal and Cutaneous Wound Healing.
    Yuan Chen, Xiaoyao Huang, Anqi Liu, Siyuan Fan, Shiyu Liu, Zihan Li, Xiaoxue Yang, Hao Guo, Meiling Wu, Meng Liu, Peisheng Liu, Fei Fu, Siying Liu, Kun Xuan.
      The interplay between bacteria and their host influences the homeostasis of the human immune microenvironment, and this reciprocal interaction also affects the process of tissue damage repair. A variety of immunomodulatory commensal bacteria reside in the body, capable of delivering membrane vesicles (MVs) to host cells to regulate the local immune microenvironment. This research revealed, for the initial time, the significant enhancement of mucosal and cutaneous wound healing by MVs secreted by the human commensal Lactobacillus reuteri (RMVs) through modulation of the inflammatory environment in wound tissue. Local administration of RMVs reduces the proportion of pro-inflammatory macrophages in inflamed tissues and mitigates the level of local inflammation, thereby facilitating the healing of oral mucosa and cutaneous wounds. The elevated oxidative stress levels in activated pro-inflammatory macrophages can be modulated by RMVs, resulting in phenotypic transformation of macrophages. Furthermore, 3-hydroxypropionaldehyde present in RMVs can decrease the mitochondrial permeability of macrophages and stabilize the mitochondrial membrane potential, thereby promoting the conversion of macrophages to an anti-inflammatory phenotype. This study pioneers the significance of commensal bacterial MVs in tissue injury repair and presents a novel concept for the repair of tissue damage.
    Keywords:  Lactobacillus reuteri DSM 20016; extracellular vesicles; macrophages; mitochondria; wound healing
    DOI:  https://doi.org/10.1002/advs.202309725
  29. ACS Sens. 2024 Apr 24.
    SERS Microsensors for the Study of pH Regulation in Cystic Fibrosis Patient-Derived Airway Cultures.
    William H Skinner, Nicola Robinson, Gareth R Hardisty, Robert D Gray, Colin J Campbell.
      Acidification of the airway surface liquid in the respiratory system could play a role in the pathology of Cystic Fibrosis, but its low volume and proximity to the airway epithelium make it a challenging biological environment in which to noninvasively collect pH measurements. To address this challenge, we explored surface enhanced Raman scattering microsensors (SERS-MS), with a 4-mercaptobenzoic acid (MBA) pH reporter molecule, as pH sensors for the airway surface liquid of patient-derived in vitro models of the human airway. Using air-liquid interface (ALI) cultures to model the respiratory epithelium, we show that SERS-MS facilitates the optical measurement of trans-epithelial pH gradients between the airway surface liquid and the basolateral culture medium. SERS-MS also enabled the successful quantification of pH changes in the airway surface liquid following stimulation of the Cystic Fibrosis transmembrane conductance regulator (CFTR, the apical ion channel that is dysfunctional in Cystic Fibrosis airways). Finally, the influence of CFTR mutations on baseline airway surface liquid pH was explored by using SERS-MS to measure the pH in ALIs grown from Cystic Fibrosis and non-Cystic Fibrosis donors.
    DOI:  https://doi.org/10.1021/acssensors.4c00279
  30. Cell Stem Cell. 2024 Apr 15. pii: S1934-5909(24)00098-5. [Epub ahead of print]
    Generation of human alveolar epithelial type I cells from pluripotent stem cells.
    Claire L Burgess, Jessie Huang, Pushpinder S Bawa, Konstantinos-Dionysios Alysandratos, Kasey Minakin, Lauren J Ayers, Michael P Morley, Apoorva Babu, Carlos Villacorta-Martin, Maria Yampolskaya, Anne Hinds, Bibek R Thapa, Feiya Wang, Adeline Matschulat, Pankaj Mehta, Edward E Morrisey, Xaralabos Varelas, Darrell N Kotton.
      Alveolar epithelial type I cells (AT1s) line the gas exchange barrier of the distal lung and have been historically challenging to isolate or maintain in cell culture. Here, we engineer a human in vitro AT1 model system via directed differentiation of induced pluripotent stem cells (iPSCs). We use primary adult AT1 global transcriptomes to suggest benchmarks and pathways, such as Hippo-LATS-YAP/TAZ signaling, enriched in these cells. Next, we generate iPSC-derived alveolar epithelial type II cells (AT2s) and find that nuclear YAP signaling is sufficient to promote a broad transcriptomic shift from AT2 to AT1 gene programs. The resulting cells express a molecular, morphologic, and functional phenotype reminiscent of human AT1 cells, including the capacity to form a flat epithelial barrier producing characteristic extracellular matrix molecules and secreted ligands. Our results provide an in vitro model of human alveolar epithelial differentiation and a potential source of human AT1s.
    Keywords:  Hippo signaling; LATS inhibition; alveolar epithelial type I cells; directed differentiation; lung; lung epithelial reporter; pluripotent stem cells
    DOI:  https://doi.org/10.1016/j.stem.2024.03.017
  31. Respir Res. 2024 Apr 25. 25(1): 180
    In vitro platform to model the function of ionocytes in the human airway epithelium.
    Marta Vilà-González, Laetitia Pinte, Ricardo Fradique, Erika Causa, Heleen Kool, Mayuree Rodrat, Carola Maria Morell, Maha Al-Thani, Linsey Porter, Wenrui Guo, Ruhina Maeshima, Stephen L Hart, Frank McCaughan, Alessandra Granata, David N Sheppard, R Andres Floto, Emma L Rawlins, Pietro Cicuta, Ludovic Vallier.
       BACKGROUND: Pulmonary ionocytes have been identified in the airway epithelium as a small population of ion transporting cells expressing high levels of CFTR (cystic fibrosis transmembrane conductance regulator), the gene mutated in cystic fibrosis. By providing an infinite source of airway epithelial cells (AECs), the use of human induced pluripotent stem cells (hiPSCs) could overcome some challenges of studying ionocytes. However, the production of AEC epithelia containing ionocytes from hiPSCs has proven difficult. Here, we present a platform to produce hiPSC-derived AECs (hiPSC-AECs) including ionocytes and investigate their role in the airway epithelium.
    METHODS: hiPSCs were differentiated into lung progenitors, which were expanded as 3D organoids and matured by air-liquid interface culture as polarised hiPSC-AEC epithelia. Using CRISPR/Cas9 technology, we generated a hiPSCs knockout (KO) for FOXI1, a transcription factor that is essential for ionocyte specification. Differences between FOXI1 KO hiPSC-AECs and their wild-type (WT) isogenic controls were investigated by assessing gene and protein expression, epithelial composition, cilia coverage and motility, pH and transepithelial barrier properties.
    RESULTS: Mature hiPSC-AEC epithelia contained basal cells, secretory cells, ciliated cells with motile cilia, pulmonary neuroendocrine cells (PNECs) and ionocytes. There was no difference between FOXI1 WT and KO hiPSCs in terms of their capacity to differentiate into airway progenitors. However, FOXI1 KO led to mature hiPSC-AEC epithelia without ionocytes with reduced capacity to produce ciliated cells.
    CONCLUSION: Our results suggest that ionocytes could have role beyond transepithelial ion transport by regulating epithelial properties and homeostasis in the airway epithelium.
    Keywords:  Airway epithelium; FOXI1; Human induced pluripotent stem cells; Ionocytes; Tissue modelling
    DOI:  https://doi.org/10.1186/s12931-024-02800-7
  32. Crit Care. 2024 Apr 22. 28(1): 133
    Lower airway microbiota compositions differ between influenza, COVID-19 and bacteria-related acute respiratory distress syndromes.
    Sébastien Imbert, Mathilde Revers, Raphaël Enaud, Arthur Orieux, Adrian Camino, Alexandre Massri, Laurent Villeneuve, Cédric Carrié, Laurent Petit, Alexandre Boyer, Patrick Berger, Didier Gruson, Laurence Delhaes, Renaud Prével.
       BACKGROUND: Acute respiratory distress syndrome (ARDS) is responsible for 400,000 deaths annually worldwide. Few improvements have been made despite five decades of research, partially because ARDS is a highly heterogeneous syndrome including various types of aetiologies. Lower airway microbiota is involved in chronic inflammatory diseases and recent data suggest that it could also play a role in ARDS. Nevertheless, whether the lower airway microbiota composition varies between the aetiologies of ARDS remain unknown. The aim of this study is to compare lower airway microbiota composition between ARDS aetiologies, i.e. pulmonary ARDS due to influenza, SARS-CoV-2 or bacterial infection.
    METHODS: Consecutive ARDS patients according to Berlin's classification requiring invasive ventilation with PCR-confirmed influenza or SARS-CoV-2 infections and bacterial infections (> 105 CFU/mL on endotracheal aspirate) were included. Endotracheal aspirate was collected at admission, V3-V4 and ITS2 regions amplified by PCR, deep-sequencing performed on MiSeq sequencer (Illumina®) and data analysed using DADA2 pipeline.
    RESULTS: Fifty-three patients were included, 24 COVID-19, 18 influenza, and 11 bacterial CAP-related ARDS. The lower airway bacteriobiota and mycobiota compositions (β-diversity) were dissimilar between the three groups (p = 0.05 and p = 0.01, respectively). The bacterial α-diversity was significantly lower in the bacterial CAP-related ARDS group compared to the COVID-19 ARDS group (p = 0.04). In contrast, influenza-related ARDS patients had higher lung mycobiota α-diversity than the COVID-19-related ARDS (p = 0 < 01).
    CONCLUSION: Composition of lower airway microbiota (both microbiota and mycobiota) differs between influenza, COVID-19 and bacterial CAP-related ARDS. Future studies investigating the role of lung microbiota in ARDS pathophysiology should take aetiology into account.
    Keywords:  Acute respiratory distress syndrome; Microbiota; Mycobiota
    DOI:  https://doi.org/10.1186/s13054-024-04922-2
  33. bioRxiv. 2024 Apr 14. pii: 2024.04.14.589416. [Epub ahead of print]
    Upper respiratory microbial communities of healthy populations are shaped by niche and age.
    Susan Zelasko, Mary Hannah Swaney, Shelby Sandstrom, Timothy C Davenport, Christine M Seroogy, James E Gern, Lindsay R Kalan, Cameron R Currie.
       Background: Alterations in upper respiratory microbiomes have been implicated in shaping host health trajectories, including by limiting mucosal pathogen colonization. However, limited comparative studies of respiratory microbiome development and functioning across age groups have been performed. Herein, we perform shotgun metagenomic sequencing paired with pathogen inhibition assays to elucidate differences in nasal and oral microbiome composition and functioning across healthy 24-month-old infant (n=229) and adult (n=100) populations.
    Results: We find that beta diversity of nasal and oral microbiomes varies with age, with nasal microbiomes showing greater population-level variation compared to oral microbiomes. Infant microbiome alpha diversity was significantly lower across nasal samples and higher in oral samples, relative to adults. Accordingly, we demonstrate significant differences in genus- and species-level composition of microbiomes between sites and age groups. Antimicrobial resistome patterns likewise varied across body sites, with oral microbiomes showing higher resistance gene abundance compared to nasal microbiomes. Biosynthetic gene clusters encoding specialized metabolite production were found in higher abundance across infant oral microbiomes, relative to adults. Investigation of pathogen inhibition revealed greater inhibition of gram-negative and gram-positive bacteria by oral commensals, while nasal isolates had higher antifungal activity.
    Conclusions: In summary, we identify significant differences in the microbial communities inhabiting nasal and oral cavities of healthy infants relative to adults. These findings inform our understanding of the interactions impacting respiratory microbiome composition and functioning, with important implications for host health across the lifespan.
    DOI:  https://doi.org/10.1101/2024.04.14.589416
  34. J Allergy Clin Immunol. 2024 Apr 24. pii: S0091-6749(24)00409-3. [Epub ahead of print]
    Antibiotics within first year are linked to infant gut microbiome disruption and elevated atopic dermatitis risk.
    Courtney Hoskinson, Maria V Medeleanu, Myrtha E Reyna, Darlene Ly Dai, Biswajit Chowdhury, Theo J Moraes, Piushkumar J Mandhane, Elinor Simons, Anita L Kozyrskyj, Meghan B Azad, Charisse Petersen, Stuart E Turvey, Padmaja Subbarao.
       BACKGROUND: Atopic dermatitis (AD) is the most common chronic inflammatory skin disease in both pediatric and adult populations. The development of AD has been linked to antibiotic usage, which causes perturbation of the microbiome and has been associated with abnormal immune system function. However, imbalances in the gut microbiome itself associated with antibiotic usage have been inconsistently linked to AD.
    OBJECTIVE: This study aimed to elucidate the timing and specific factors mediating the relationship between systemic (oral or intravenous) antibiotic usage and AD.
    METHODS: We used statistical modelling and differential analysis to link CHILD participants' history of antibiotic usage and early-life gut microbiome alterations to atopic dermatitis.
    RESULTS: Here we report that systemic antibiotics during the first year of life, as compared to later, are associated with AD risk (adjusted odds ratio (aOR) = 1.81 [95% CI = 1.28 - 2.57], p < 0.001), with an increased number of antibiotic courses corresponding to a dose-response-like increased risk of AD risk (1 course: aOR = 1.67 [95% CI = 1.17 - 2.38]; 2 or more courses: aOR = 2.16 [95% CI = 1.30 - 3.59]). Further, we demonstrate that microbiome alterations associated with both AD and systemic antibiotic usage fully mediate the effect of antibiotic usage on the development of AD (βindirect = 0.072, p < 0.001). Alterations in the 1-year infant gut microbiome of participants who would later develop AD included increased Tyzzerella nexilis, increased monosaccharide utilization, and parallel decreased Bifidobacterium, Eubacterium spp., and fermentative pathways.
    CONCLUSION: Our findings indicate that early-life antibiotic usage, especially in the first year of life, modulates key gut microbiome components that may be used as markers to predict and possibly prevent the development of AD.
    Keywords:  Atopic dermatitis; antibiotics; microbiome
    DOI:  https://doi.org/10.1016/j.jaci.2024.03.025
  35. Chin Med J Pulm Crit Care Med. 2024 Mar;2(1): 17-26
    Epithelial stem cells and niches in lung alveolar regeneration and diseases.
    Jilei Zhang, Yuru Liu.
      Alveoli serve as the functional units of the lungs, responsible for the critical task of blood-gas exchange. Comprising type I (AT1) and type II (AT2) cells, the alveolar epithelium is continuously subject to external aggressors like pathogens and airborne particles. As such, preserving lung function requires both the homeostatic renewal and reparative regeneration of this epithelial layer. Dysfunctions in these processes contribute to various lung diseases. Recent research has pinpointed specific cell subgroups that act as potential stem or progenitor cells for the alveolar epithelium during both homeostasis and regeneration. Additionally, endothelial cells, fibroblasts, and immune cells synergistically establish a nurturing microenvironment-or "niche"-that modulates these epithelial stem cells. This review aims to consolidate the latest findings on the identities of these stem cells and the components of their niche, as well as the molecular mechanisms that govern them. Additionally, this article highlights diseases that arise due to perturbations in stem cell-niche interactions. We also discuss recent technical innovations that have catalyzed these discoveries. Specifically, this review underscores the heterogeneity, plasticity, and dynamic regulation of these stem cell-niche systems. It is our aspiration that a deeper understanding of the fundamental cellular and molecular mechanisms underlying alveolar homeostasis and regeneration will open avenues for identifying novel therapeutic targets for conditions such as chronic obstructive pulmonary disease (COPD), fibrosis, coronavirus disease 2019 (COVID-19), and lung cancer.
    Keywords:  Alveoli; Epithelium; Niche; Stem cell; Type II cell (AT2)
    DOI:  https://doi.org/10.1016/j.pccm.2023.10.007
  36. Adv Sci (Weinh). 2024 Apr 26. e2307545
    Exploring Memory Function Beyond Immune Cells: ANGPTL4-Mediated Memory Functions in Tissue Resident Stem Cells.
    Se-Ra Park, Eun-Kyung Min, Soo-Rim Kim, Suk-Kyung Kim, Kun-Hee Na, Chan Hum Park, YunJae Jung, Byung-Chul Oh, In-Sun Hong.
      Adapted immune cells are known to develop memory functions that increase resistance to subsequent infections after initial pathogen exposure, however, it is unclear whether non-immune cells, like tissue-resident stem cells, have similar memory functions. Here, it is found that tissue-resident stem cells crucial for tissue regeneration show diminished adverse effects on diverse stem cell functions against successive exposure to foreign antigen (β-glucan) to maintain tissue homeostasis and stability both in vitro and in vivo. These data suggest that endometrial stem cells may possess a robust memory function, in contrast, fully differentiated cells like fibroblasts and vesicular cells do not show these memory mechanisms upon consecutive antigen exposure. Moreover, the pivotal role of Angiopoietin-like 4 (ANGPTL4) in regulating the memory functions of endometrial stem cells is identified through specific shRNA knockdown in vitro and knockout mice in vivo experiments. ANGPTL4 is associated with the alteration of diverse stem cell functions and epigenetic modifications, notably through histone H3 methylation changes and two pathways (i.e., PI3K/Akt and FAK/ERK1/2 signaling) upon consecutive antigen exposure. These findings imply the existence of inherent self-defense mechanisms through which local stem cells can adapt and protect themselves from recurrent antigenic challenges, ultimately mitigating adverse consequences.
    Keywords:  ANGPTL4; endometrial stem cells; foreign antigen; memory function
    DOI:  https://doi.org/10.1002/advs.202307545
  37. Cell Host Microbe. 2024 Apr 22. pii: S1931-3128(24)00121-5. [Epub ahead of print]
    Microbiota metabolism of intestinal amino acids impacts host nutrient homeostasis and physiology.
    JRI Live Cell Bank Consortium
      The intestine and liver are thought to metabolize dietary nutrients and regulate host nutrient homeostasis. Here, we find that the gut microbiota also reshapes the host amino acid (aa) landscape via efficiently metabolizing intestinal aa. To identify the responsible microbes/genes, we developed a metabolomics-based assay to screen 104 commensals and identified candidates that efficiently utilize aa. Using genetics, we identified multiple responsible metabolic genes in phylogenetically diverse microbes. By colonizing germ-free mice with the wild-type strain and their isogenic mutant deficient in individual aa-metabolizing genes, we found that these genes regulate the availability of gut and circulatory aa. Notably, microbiota genes for branched-chain amino acids (BCAAs) and tryptophan metabolism indirectly affect host glucose homeostasis via peripheral serotonin. Collectively, at single-gene level, this work characterizes a microbiota-encoded metabolic activity that affects host nutrient homeostasis and provides a roadmap to interrogate microbiota-dependent activity to improve human health.
    Keywords:  amino acid metabolism; glucose tolerance; gut microbiota and metabolic genes; human microbiota
    DOI:  https://doi.org/10.1016/j.chom.2024.04.004
  38. Int Immunopharmacol. 2024 Apr 23. pii: S1567-5769(24)00530-7. [Epub ahead of print]133 112012
    Mitochondrial-dependent oxidative phosphorylation is key for postnatal metabolic adaptation of alveolar macrophages in the lung.
    Jun Zhang, Yu Peng, Haosen Song, Siqi Liu, Chuanwei Li, Yi Zhang, Xiaowei Shi, Huifang Guo, Yingping Xu.
      Alveolar macrophages (AMs) seed in lung during embryogenesis and become mature in perinatal period. Establishment of acclimatization to environmental challenges is important, whereas the detailed mechanisms that drive metabolic adaptation of AMs remains to be elucidated. Here, we showed that energy metabolism of AMs was transformed from glycolysis prenatally to oxidative phosphorylation (OXPHOS) postnatally accompanied by up-regulated expression of mitochondrial transcription factor A (TFAM). TFAM deficiency disturbed mitochondrial stability and decreased OXPHOS, which finally impaired AM maintenance and function, but not AM embryonic development. Mechanistically, Tfam-deletion resulted in impaired mitochondrial respiration and decreased ATP production, which triggered endoplasmic reticulum (ER) stress to cause B cell lymphoma 2 ovarian killer (BOK) accumulation and abnormal distribution of intracellular Ca2+, eventually led to induce AM apoptotic death. Thus, our data illustrated mitochondrial-dependent OXPHOS played a key role in orchestrating AM postnatal metabolic adaptation.
    Keywords:  Alveolar macrophages; Endoplasmic reticulum stress; Metabolic adaptation; mitochondrial transcription factor A
    DOI:  https://doi.org/10.1016/j.intimp.2024.112012
  39. Adv Drug Deliv Rev. 2024 Apr 24. pii: S0169-409X(24)00137-6. [Epub ahead of print] 115315
    Advancing immunotherapy using biomaterials to control tissue, cellular, and molecular level immune signaling in skin.
    Shrey A Shah, Robert S Oakes, Christopher M Jewell.
      Immunotherapies have been transformative in many areas, including cancer treatments, allergies, and autoimmune diseases. However, significant challenges persist in extending the reach of these technologies to new indications and patients. Some of the major hurdles include narrow applicability to patient groups, transient efficacy, high cost burdens, poor immunogenicity, and side effects or off-target toxicity that results from lack of disease-specificity and inefficient delivery. Thus, there is a significant need for strategies that control immune responses generated by immunotherapies while targeting infection, cancer, allergy, and autoimmunity. Being the outermost barrier of the body and the first line of host defense, the skin presents a unique immunological interface to achieve these goals. The skin contains a high concentration of specialized immune cells, such as antigen-presenting cells and tissue-resident memory T cells. These cells feature diverse and potent combinations of immune receptors, providing access to cellular and molecular level control to modulate immune responses. Thus, skin provides accessible tissue, cellular, and molecular level controls that can be harnessed to improve immunotherapies. Biomaterial platforms - microneedles, nano- and micro-particles, scaffolds, and other technologies - are uniquely capable of modulating the specialized immunological niche in skin by targeting these distinct biological levels of control. This review highlights recent pre-clinical and clinical advances in biomaterial-based approaches to target and modulate skin immune signaling at the tissue, cellular, and molecular levels for immunotherapeutic applications. We begin by discussing skin cytoarchitecture and resident immune cells to establish the biological rationale for skin-targeting immunotherapies. This is followed by a critical presentation of biomaterial-based pre-clinical and clinical studies aimed at controlling the immune response in the skin for immunotherapy and therapeutic vaccine applications in cancer, allergy, and autoimmunity.
    Keywords:  And autoimmunity; Biomaterial and microneedle; Cancer; Inflammation and tolerance; Skin; Vaccine and immunotherapy
    DOI:  https://doi.org/10.1016/j.addr.2024.115315
  40. Microlife. 2024 ;5 uqae008
    Meeting report 'Microbiology 2023: from single cell to microbiome and host', an international interacademy conference in Würzburg.
    Pascale Cossart, Jörg Hacker, David H Holden, Staffan Normark, Jörg Vogel.
      On September 20-22 September 2023, the international conference 'Microbiology 2023: from single cell to microbiome and host' convened microbiologists from across the globe for a very successful symposium, showcasing cutting-edge research in the field. Invited lecturers delivered exceptional presentations covering a wide range of topics, with a major emphasis on phages and microbiomes, on the relevant bacteria within these ecosystems, and their multifaceted roles in diverse environments. Discussions also spanned the intricate analysis of fundamental bacterial processes, such as cell division, stress resistance, and interactions with phages. Organized by four renowned Academies, the German Leopoldina, the French Académie des sciences, the Royal Society UK, and the Royal Swedish Academy of Sciences, the symposium provided a dynamic platform for experts to share insights and discoveries, leaving participants inspired and eager to integrate new knowledge into their respective projects. The success of Microbiology 2023 prompted the decision to host the next quadrennial academic meeting in Sweden. This choice underscores the commitment to fostering international collaboration and advancing the frontiers of microbiological knowledge. The transition to Sweden promises to be an exciting step in the ongoing global dialogue and specific collaborations on microbiology, a field where researchers will continue to push the boundaries of knowledge, understanding, and innovation not only in health and disease but also in ecology.
    Keywords:  bacterial immunity; host–microbe interaction; infection biology; microbiology; microbiome; pathogen–phage interaction
    DOI:  https://doi.org/10.1093/femsml/uqae008
  41. Nature. 2024 Apr 24.
    Periportal macrophages protect against commensal-driven liver inflammation.
    Yu Miyamoto, Junichi Kikuta, Takahiro Matsui, Tetsuo Hasegawa, Kentaro Fujii, Daisuke Okuzaki, Yu-Chen Liu, Takuya Yoshioka, Shigeto Seno, Daisuke Motooka, Yutaka Uchida, Erika Yamashita, Shogo Kobayashi, Hidetoshi Eguchi, Eiichi Morii, Karl Tryggvason, Takashi Shichita, Hisako Kayama, Koji Atarashi, Jun Kunisawa, Kenya Honda, Kiyoshi Takeda, Masaru Ishii.
      The liver is the main gateway from the gut, and the unidirectional sinusoidal flow from portal to central veins constitutes heterogenous zones, including the periportal vein (PV) and the pericentral vein zones1-5. However, functional differences in the immune system in each zone remain poorly understood. Here intravital imaging revealed that inflammatory responses are suppressed in PV zones. Zone-specific single-cell transcriptomics detected a subset of immunosuppressive macrophages enriched in PV zones that express high levels of interleukin-10 and Marco, a scavenger receptor that sequesters pro-inflammatory pathogen-associated molecular patterns and damage-associated molecular patterns, and consequently suppress immune responses. Induction of Marco+ immunosuppressive macrophages depended on gut microbiota. In particular, a specific bacterial family, Odoribacteraceae, was identified to induce this macrophage subset through its postbiotic isoallolithocholic acid. Intestinal barrier leakage resulted in inflammation in PV zones, which was markedly augmented in Marco-deficient conditions. Chronic liver inflammatory diseases such as primary sclerosing cholangitis (PSC) and non-alcoholic steatohepatitis (NASH) showed decreased numbers of Marco+ macrophages. Functional ablation of Marco+ macrophages led to PSC-like inflammatory phenotypes related to colitis and exacerbated steatosis in NASH in animal experimental models. Collectively, commensal bacteria induce Marco+ immunosuppressive macrophages, which consequently limit excessive inflammation at the gateway of the liver. Failure of this self-limiting system promotes hepatic inflammatory disorders such as PSC and NASH.
    DOI:  https://doi.org/10.1038/s41586-024-07372-6
  42. bioRxiv. 2024 Mar 31. pii: 2024.03.28.587272. [Epub ahead of print]
    IL-10 dependent adaptation allows macrophages to adjust inflammatory responses to TLR4 stimulation history.
    H Bongartz, C Bradfield, J Gross, I D C Fraser, A Nita-Lazar, M Meier-Schellersheim.
      During an infection, innate immune cells must adjust nature and strength of their responses to changing pathogen abundances. To determine how stimulation of the pathogen sensing TLR4 shapes subsequent macrophage responses, we systematically varied priming and restimulation concentrations of its ligand KLA. We find that different priming strengths have very distinct effects at multiple stages of the signaling response, including receptor internalization, MAPK activation, cytokine and chemokine production, and nuclear translocation and chromatin association of NFκB and IκB members. In particular, restimulation-induced TNF-α production required KLA doses equal to or greater than those used for prior exposure, indicating that macrophages can detect and adaptively respond to changing TLR4 stimuli. Interestingly, while such adaptation was dependent on the anti-inflammatory cytokine IL-10, exogenous concentrations of IL-10 corresponding to those secreted after strong priming did not exert suppressive effects on TNF-α without such prior priming, confirming the critical role of TLR4 stimulation history.
    DOI:  https://doi.org/10.1101/2024.03.28.587272
  43. Heliyon. 2024 Apr 30. 10(8): e29588
    The effect of probiotic Bifidobacterium lactis Bl-04 on innate antiviral responses invitro.
    Sinikka Latvala, Markus J Lehtinen, Sanna M Mäkelä, Derek Nedveck, Bryan Zabel, Ilmari Ahonen, Liisa Lehtoranta, Ronald B Turner, Jenni Liljavirta.
      Consumption of certain probiotic strains may be beneficial for reducing the risk of acute upper respiratory tract infections (URTIs), however, underlying immunological mechanisms are elusive. Bifidobacterium lactis Bl-04™ has been reported in humans to significantly reduce the risk of URTIs, affect the innate immunity in the nasal mucosa, and reduce nasal lavage virus titer after a rhinovirus (RV) challenge. To study the immunological mechanisms, we investigated the effect of Bl-04 on cytokine production and transcriptomes of human monocyte-derived macrophages (Mfs) and dendritic cells (DCs), and further on RV replication and cytokine production in MRC-5 fibroblasts. The results showed that Bl-04 modulates antiviral immune responses and potentiates cytokine production during viral challenge mimic in immune cells. However, effect of Bl-04 on RV replication and cytokine production in fibroblasts was negligible. Overall, the findings suggest that Bl-04 mildly stimulates antiviral immunity in Mfs and DCs, and potentially influences viral replication in fibroblasts that however warrants further investigations.
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e29588
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