bims-bac4me 2023-06-18 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2023–06–18
23 papers selected by
Chun-Chi Chang, Universitäts Spital Zürich

Development of innate immune memory by non-immune cells during Staphylococcus aureus infection depends on reactive oxygen species.
Commensal colonization reduces Pseudomonas aeruginosa burden and subsequent airway damage.
Advances in immune response to pulmonary infection: Nonspecificity, specificity and memory.
Trained immunity in atherosclerotic cardiovascular disease.
Dimethyl fumarate and 4-octyl itaconate are anticoagulants that suppress Tissue Factor in macrophages via inhibition of Type I Interferon.
Rapid Reduction in Staphylococcus aureus in Atopic Dermatitis Subjects Following Dupilumab Treatment.
Neutrophil-intrinsic TNF receptor signaling orchestrates host defense against Staphylococcus aureus.
Re-recognition of innate immune memory as an integrated multidimensional concept.
New insights into inflammatory memory of epidermal stem cells.
Interactions between the lung microbiome and host immunity in chronic obstructive pulmonary disease.
Probiotics and Commensal Bacteria Metabolites Trigger Epigenetic Changes in the Gut and Influence Beneficial Mood Dispositions.
Type I Interferon Signaling on Antigen-Presenting Cells Blunts Cell-Mediated Immunity toward Listeria monocytogenes.
Moderate exercise induces trained immunity in macrophages.
Regulation of systemic metabolism by tissue-resident immune cell circuits.
Activation of regulatory dendritic cells by Mertk coincides with a temporal wave of apoptosis in neonatal lungs.
A role for fibroblast-derived SASP factors in the activation of pyroptotic cell death in mammary epithelial cells.
Protocol for generating airway organoids from 2D air liquid interface-differentiated nasal epithelia for use in a functional CFTR assay.
The role of the respiratory microbiome in asthma.
Oral Administration of Lacticaseibacillus rhamnosus CRL1505 Modulates Lung Innate Immune Response against Klebsiella pneumoniae ST25.
Editorial: Insights in microbial immunology: 2022.
Integration of immune cells in organs-on-chips: a tutorial.
Interleukin-1 family cytokines at the crossroads of microbiome regulation in barrier health and disease.
Altered Respiratory Microbiomes, Plasma Metabolites, and Immune Responses in Influenza A Virus and Methicillin-Resistant Staphylococcus aureus Coinfection.

Front Immunol. 2023 ;14 1138539

Development of innate immune memory by non-immune cells during Staphylococcus aureus infection depends on reactive oxygen species.

Emmanuel Chaumond, Sandrine Peron, Nathalie Daniel, Yann Le Gouar, Éric Guédon, David L Williams, Yves Le Loir, Gwénaël Jan, Nadia Berkova.

   Introduction: The mechanisms underlying innate immune memory (trained immunity) comprise epigenetic reprogramming of transcriptional pathways associated with alterations of intracellular metabolism. While the mechanisms of innate immune memory carried out by immune cells are well characterized, such processes in non-immune cells, are poorly understood. The opportunistic pathogen, Staphylococcus aureus, is responsible for a multitude of human diseases, including pneumonia, endocarditis and osteomyelitis, as well as animal infections, including chronic cattle mastitis that are extremely difficult to treat. An induction of innate immune memory may be considered as a therapeutic alternative to fight S. aureus infection.
Methods: In the current work, we demonstrated the development of innate immune memory in non-immune cells during S. aureus infection employing a combination of techniques including Enzyme-linked immunosorbent assay (ELISA), microscopic analysis, and cytometry.
Results: We observed that training of human osteoblast-like MG-63 cells and lung epithelial A549 cells with β-glucan increased IL-6 and IL-8 production upon a stimulation with S. aureus, concomitant with histones modifications. IL-6 and IL-8 production was positively correlated with an acetylation of histone 3 at lysine 27 (H3K27), thus suggesting epigenetic reprogramming in these cells. An addition of the ROS scavenger N-Acetylcysteine, NAC, prior to β-glucan pretreatment followed by an exposure to S. aureus, resulted in decreased IL-6 and IL-8 production, thereby supporting the involvement of ROS in the induction of innate immune memory. Exposure of cells to Lactococcus lactis resulted in increased IL-6 and IL-8 production by MG-63 and A549 cells upon a stimulation with S. aureus that was correlated with H3K27 acetylation, suggesting the ability of this beneficial bacterium to induce innate immune memory.
Discussion: This work improves our understanding of innate immune memory in non-immune cells in the context of S. aureus infection. In addition to known inducers, probiotics may represent good candidates for the induction of innate immune memory. Our findings may help the development of alternative therapeutic approaches for the prevention of S. aureus infection.

Keywords:  Lactococcus lactis; Staphylococcus aureus; epigenetics; immune response; innate immune memory; non-immune cells; reactive oxygen species

DOI:  https://doi.org/10.3389/fimmu.2023.1138539
Front Cell Infect Microbiol. 2023 ;13 1144157

Commensal colonization reduces Pseudomonas aeruginosa burden and subsequent airway damage.

Sara N Stoner, Joshua J Baty, Lea Novak, Jessica A Scoffield.

  Pseudomonas aeruginosa dominates the complex polymicrobial cystic fibrosis (CF) airway and is a leading cause of death in persons with CF. Interestingly, oral streptococcal colonization has been associated with stable CF lung function. The most abundant streptococcal species found in stable patients, Streptococcus salivarius, has been shown to downregulate pro-inflammatory cytokines in multiple colonization models. However, no studies have demonstrated how S. salivarius potentially improves lung function. Our lab previously demonstrated that the P. aeruginosa exopolysaccharide Psl promotes S. salivarius biofilm formation in vitro, suggesting a possible mechanism by which S. salivarius is incorporated into the CF airway microbial community. In this study, we demonstrate that co-infection of rats leads to enhanced S. salivarius colonization and reduced P. aeruginosa colonization. Histological scores for tissue inflammation and damage are lower in dual-infected rats compared to P. aeruginosa infected rats. Additionally, pro-inflammatory cytokines IL-1β, IL-6, CXCL2, and TNF-α are downregulated during co-infection compared to P. aeruginosa single-infection. Lastly, RNA sequencing of cultures grown in synthetic CF sputum revealed that P. aeruginosa glucose metabolism genes are downregulated in the presence of S. salivarius, suggesting a potential alteration in P. aeruginosa fitness during co-culture. Overall, our data support a model in which S. salivarius colonization is promoted during co-infection with P. aeruginosa, whereas P. aeruginosa airway bacterial burden is reduced, leading to an attenuated host inflammatory response.

Keywords:  Pseudomonas aeruginosa; Streptococcus salivarius; commensal; cystic fibrosis; oral commensal bacteria; polymicrobial; streptococci

DOI:  https://doi.org/10.3389/fcimb.2023.1144157
Chronic Dis Transl Med. 2023 Jun;9(2): 71-81

Advances in immune response to pulmonary infection: Nonspecificity, specificity and memory.

Jianqiao Xu, Lixin Xie.

  The lung immune response consists of various cells involved in both innate and adaptive immune processes. Innate immunity participates in immune resistance in a nonspecific manner, whereas adaptive immunity effectively eliminates pathogens through specific recognition. It was previously believed that adaptive immune memory plays a leading role during secondary infections; however, innate immunity is also involved in immune memory. Trained immunity refers to the long-term functional reprogramming of innate immune cells caused by the first infection, which alters the immune response during the second challenge. Tissue resilience limits the tissue damage caused by infection by controlling excessive inflammation and promoting tissue repair. In this review, we summarize the impact of host immunity on the pathophysiological processes of pulmonary infections and discuss the latest progress in this regard. In addition to the factors influencing pathogenic microorganisms, we emphasize the importance of the host response.

Keywords:  adaptive immunity; innate immunity; lung infection; trained immunity

DOI:  https://doi.org/10.1002/cdt3.71
Nat Rev Cardiol. 2023 Jun 15.

Trained immunity in atherosclerotic cardiovascular disease.

Niels P Riksen, Siroon Bekkering, Willem J M Mulder, Mihai G Netea.

Trained immunity, also known as innate immune memory, is a persistent hyper-responsive functional state of innate immune cells. Accumulating evidence implicates trained immunity as an underlying mechanism of chronic inflammation in atherosclerotic cardiovascular disease. In this context, trained immunity is induced by endogenous atherosclerosis-promoting factors, such as modified lipoproteins or hyperglycaemia, causing broad metabolic and epigenetic reprogramming of the myeloid cell compartment. In addition to traditional cardiovascular risk factors, lifestyle factors, including unhealthy diets, sedentary lifestyle, sleep deprivation and psychosocial stress, as well as inflammatory comorbidities, have been shown to activate trained immunity-like mechanisms in bone marrow haematopoietic stem cells. In this Review, we discuss the molecular and cellular mechanisms of trained immunity, its systemic regulation through haematopoietic progenitor cells in the bone marrow, and the activation of these mechanisms by cardiovascular disease risk factors. We also highlight other trained immunity features that are relevant for atherosclerotic cardiovascular disease, including the diverse cell types that show memory characteristics and transgenerational inheritance of trained immunity traits. Finally, we propose potential strategies for the therapeutic modulation of trained immunity to manage atherosclerotic cardiovascular disease.

DOI: https://doi.org/10.1038/s41569-023-00894-y
Nat Commun. 2023 Jun 14. 14(1): 3513

Dimethyl fumarate and 4-octyl itaconate are anticoagulants that suppress Tissue Factor in macrophages via inhibition of Type I Interferon.

Tristram A J Ryan, Alexander Hooftman, Aisling M Rehill, Matt D Johansen, Eóin C O' Brien, Juliana E Toller-Kawahisa, Mieszko M Wilk, Emily A Day, Hauke J Weiss, Pourya Sarvari, Emilio G Vozza, Fabian Schramm, Christian G Peace, Alessia Zotta, Stefan Miemczyk, Christina Nalkurthi, Nicole G Hansbro, Gavin McManus, Laura O'Doherty, Siobhan Gargan, Aideen Long, Jean Dunne, Clíona Ní Cheallaigh, Niall Conlon, Michael Carty, Padraic G Fallon, Kingston H G Mills, Emma M Creagh, James S O' Donnell, Paul J Hertzog, Philip M Hansbro, Rachel M McLoughlin, Małgorzata Wygrecka, Roger J S Preston, Zbigniew Zasłona, Luke A J O' Neill.

Excessive inflammation-associated coagulation is a feature of infectious diseases, occurring in such conditions as bacterial sepsis and COVID-19. It can lead to disseminated intravascular coagulation, one of the leading causes of mortality worldwide. Recently, type I interferon (IFN) signaling has been shown to be required for tissue factor (TF; gene name F3) release from macrophages, a critical initiator of coagulation, providing an important mechanistic link between innate immunity and coagulation. The mechanism of release involves type I IFN-induced caspase-11 which promotes macrophage pyroptosis. Here we find that F3 is a type I IFN-stimulated gene. Furthermore, F3 induction by lipopolysaccharide (LPS) is inhibited by the anti-inflammatory agents dimethyl fumarate (DMF) and 4-octyl itaconate (4-OI). Mechanistically, inhibition of F3 by DMF and 4-OI involves suppression of Ifnb1 expression. Additionally, they block type I IFN- and caspase-11-mediated macrophage pyroptosis, and subsequent TF release. Thereby, DMF and 4-OI inhibit TF-dependent thrombin generation. In vivo, DMF and 4-OI suppress TF-dependent thrombin generation, pulmonary thromboinflammation, and lethality induced by LPS, E. coli, and S. aureus, with 4-OI additionally attenuating inflammation-associated coagulation in a model of SARS-CoV-2 infection. Our results identify the clinically approved drug DMF and the pre-clinical tool compound 4-OI as anticoagulants that inhibit TF-mediated coagulopathy via inhibition of the macrophage type I IFN-TF axis.

DOI: https://doi.org/10.1038/s41467-023-39174-1
J Allergy Clin Immunol. 2023 Jun 12. pii: S0091-6749(23)00754-6. [Epub ahead of print]

Rapid Reduction in Staphylococcus aureus in Atopic Dermatitis Subjects Following Dupilumab Treatment.

Eric L Simpson, Patrick M Schlievert, Takeshi Yoshida, Stephanie Lussier, Mark Boguniewicz, Tissa Hata, Zelma Fuxench, Anna De Benedetto, Peck Y Ong, Justin Ko, Agustin Calatroni, Amanda K Rudman Spergel, Marshall Plaut, Sally A Quataert, Samuel H Kilgore, Liam Peterson, Ann L Gill, Gloria David, Tim Mosmann, Steven R Gill, Donald Y M Leung, Lisa A Beck.

   BACKGROUND: Atopic dermatitis (AD) is an inflammatory disorder characterized by dominant type 2 inflammation leading to chronic pruritic skin lesions, allergic comorbidities and Staphylococcus aureus skin colonization and infections. S. aureus is thought to play a role in AD severity.
OBJECTIVE: We characterized the changes in the host-microbial interface in AD subjects following type 2 blockade with dupilumab.
METHODS: Participants (n=71) with moderate-severe AD were enrolled in a randomized (dupilumab vs placebo; 2:1), double-blind study at Atopic Dermatitis Research Network centers. Bioassays were performed at multiple timepoints: S. aureus and virulence factor quantification, 16s rRNA microbiome, serum biomarkers, skin transcriptomic analyses and peripheral blood T-cell phenotyping.
RESULTS: At baseline, 100% of participants were S. aureus colonized on the skin surface. Dupilumab treatment resulted in significant reductions in S. aureus after only 3 days (compared to placebo); 11 days before clinical improvement. Participants with the greatest S. aureus reductions had the best clinical outcomes, and these reductions correlated with reductions in serum CCL17 and disease severity. Reductions (10-fold) in S. aureus cytotoxins (day 7), perturbations in Th17 subsets (day 14), and increased expression of genes relevant for IL-17, neutrophil and complement pathways (day 7) were also observed.
CONCLUSION: Blockade of IL-4 and IL-13 signaling, very rapidly (day 3) reduces S. aureus abundance in AD subjects, and this reduction correlates with reductions in the type 2 biomarker, CCL17 and measures of AD severity (excluding itch). Immunoprofiling and/or transcriptomics suggest a role for Th17, neutrophils and complement activation as potential mechanisms to explain these findings.

Keywords:  Atopic dermatitis; Staphylococcus aureus; barrier; cytotoxins; dupilumab; interleukin-13; interleukin-17; interleukin-4; microbiome; type 2 immunity

DOI:  https://doi.org/10.1016/j.jaci.2023.05.026
Sci Adv. 2023 Jun 16. 9(24): eadf8748

Neutrophil-intrinsic TNF receptor signaling orchestrates host defense against Staphylococcus aureus.

Christine Youn, Cristina Pontaza, Yu Wang, Dustin A Dikeman, Daniel P Joyce, Martin P Alphonse, Meng-Jen Wu, Sabrina J Nolan, Mohamed A Anany, Michael Ahmadi, Jeremy Young, Aron Tocaj, Luis A Garza, Harald Wajant, Lloyd S Miller, Nathan K Archer.

Staphylococcus aureus is the leading cause of skin and soft tissue infections and is a major health burden due to the emergence of antibiotic-resistant strains. To address the unmet need of alternative treatments to antibiotics, a better understanding of the protective immune mechanisms against S. aureus skin infection is warranted. Here, we report that tumor necrosis factor (TNF) promoted protection against S. aureus in the skin, which was mediated by bone marrow-derived immune cells. Furthermore, neutrophil-intrinsic TNF receptor (TNFR) signaling directed immunity against S. aureus skin infections. Mechanistically, TNFR1 promoted neutrophil recruitment to the skin, whereas TNFR2 prevented systemic bacterial dissemination and directed neutrophil antimicrobial functions. Treatment with a TNFR2 agonist showed therapeutic efficacy against S. aureus and Pseudomonas aeruginosa skin infections, which involved increased neutrophil extracellular trap formation. Our findings revealed nonredundant roles for TNFR1 and TNFR2 in neutrophils for immunity against S. aureus and can be therapeutically targeted for protection against bacterial skin infections.

DOI: https://doi.org/10.1126/sciadv.adf8748
Microbiol Immunol. 2023 Jun 13.

Re-recognition of innate immune memory as an integrated multidimensional concept.

Chang Tang, Shoichiro Kurata, Naoyuki Fuse.

  In the past decade, the concept of immunological memory, which has long been considered a phenomenon observed in the adaptive immunity of vertebrates, has been extended to the innate immune system of various organisms. This de novo immunological memory is mainly called "innate immune memory", "immune priming", or "trained immunity" and has received increased attention because of its potential for clinical and agricultural applications. However, research on different species, especially invertebrates and vertebrates, has caused controversy regarding this concept. Here we discuss the current studies focusing on this immunological memory and summarize several mechanisms underlying it. We propose "innate immune memory" as a multidimensional concept as an integration between the seemingly different immunological phenomena.

Keywords:  epigenetics; immune priming; innate immune memory; metabolism; trained immunity

DOI:  https://doi.org/10.1111/1348-0421.13083
Front Immunol. 2023 ;14 1188559

New insights into inflammatory memory of epidermal stem cells.

Dapeng Cheng, Xiaochen Zhu, Shaochen Yan, Linli Shi, Zhi Liu, Xin Zhou, Xinling Bi.

  Inflammatory memory, as one form of innate immune memory, has a wide range of manifestations, and its occurrence is related to cell epigenetic modification or metabolic transformation. When re-encountering similar stimuli, executing cells with inflammatory memory function show enhanced or tolerated inflammatory response. Studies have identified that not only hematopoietic stem cells and fibroblasts have immune memory effects, but also stem cells from various barrier epithelial tissues generate and maintain inflammatory memory. Epidermal stem cells, especially hair follicle stem cells, play an essential role in wound healing, immune-related skin diseases, and skin cancer development. In recent years, it has been found that epidermal stem cells from hair follicle can remember the inflammatory response and implement a more rapid response to subsequent stimuli. This review updates the advances of inflammatory memory and focuses on its mechanisms in epidermal stem cells. We are finally looking forward to further research on inflammatory memory, which will allow for the development of precise strategies to manipulate host responses to infection, injury, and inflammatory skin disease.

Keywords:  chromatin accessibility; epidermal stem cells; epigenetic memory; hair follicular bulge; inflammatory memory

DOI:  https://doi.org/10.3389/fimmu.2023.1188559
Chronic Dis Transl Med. 2023 Jun;9(2): 104-121

Interactions between the lung microbiome and host immunity in chronic obstructive pulmonary disease.

Yixing Zhu, De Chang.

  Chronic obstructive pulmonary disease (COPD) is a common chronic respiratory disease and the third leading cause of death worldwide. Developments in next-generation sequencing technology have improved microbiome analysis, which is increasingly recognized as an important component of disease management. Similar to the gut, the lung is a biosphere containing billions of microbial communities. The lung microbiome plays an important role in regulating and maintaining the host immune system. The microbiome composition, metabolites of microorganisms, and the interactions between the lung microbiome and the host immunity profoundly affect the occurrence, development, treatment, and prognosis of COPD. In this review, we drew comparisons between the lung microbiome of healthy individuals and that of patients with COPD. Furthermore, we summarize the intrinsic interactions between the host and the overall lung microbiome, focusing on the underlying mechanisms linking the microbiome to the host innate and adaptive immune response pathways. Finally, we discuss the possibility of using the microbiome as a biomarker to determine the stage and prognosis of COPD and the feasibility of developing a novel, safe, and effective therapeutic target.

Keywords:  adaptive immune response; chronic obstructive pulmonary disease; innate immune response; microbiome

DOI:  https://doi.org/10.1002/cdt3.66
Microorganisms. 2023 May 18. pii: 1334. [Epub ahead of print]11(5):

Probiotics and Commensal Bacteria Metabolites Trigger Epigenetic Changes in the Gut and Influence Beneficial Mood Dispositions.

Luis Vitetta, Matthew Bambling, Esben Strodl.

  The effect of the intestinal microbiome on the gut-brain axis has received considerable attention, strengthening the evidence that intestinal bacteria influence emotions and behavior. The colonic microbiome is important to health and the pattern of composition and concentration varies extensively in complexity from birth to adulthood. That is, host genetics and environmental factors are complicit in shaping the development of the intestinal microbiome to achieve immunological tolerance and metabolic homeostasis from birth. Given that the intestinal microbiome perseveres to maintain gut homeostasis throughout the life cycle, epigenetic actions may determine the effect on the gut-brain axis and the beneficial outcomes on mood. Probiotics are postulated to exhibit a range of positive health benefits including immunomodulating capabilities. Lactobacillus and Bifidobacterium are genera of bacteria found in the intestines and so far, the benefits afforded by ingesting bacteria such as these as probiotics to people with mood disorders have varied in efficacy. Most likely, the efficacy of probiotic bacteria at improving mood has a multifactorial dependency, relying namely on several factors that include the agents used, the dose, the pattern of dosing, the pharmacotherapy used, the characteristics of the host and the underlying luminal microbial environment (e.g., gut dysbiosis). Clarifying the pathways linking probiotics with improvements in mood may help identify the factors that efficacy is dependent upon. Adjunctive therapies with probiotics for mood disorders could, through DNA methylation molecular mechanisms, augment the intestinal microbial active cohort and endow its mammalian host with important and critical co-evolutionary redox signaling metabolic interactions, that are embedded in bacterial genomes, and that in turn can enhance beneficial mood dispositions.

Keywords:  Bifidobacterium; Lactobacillus; bio-therapeutics; enteric viruses; epigenetics; gut dysbiosis; immunomodulation; inflammation; major depression; prebiotics; probiotics

DOI:  https://doi.org/10.3390/microorganisms11051334
Infect Immun. 2023 Jun 12. e0054022

Type I Interferon Signaling on Antigen-Presenting Cells Blunts Cell-Mediated Immunity toward Listeria monocytogenes.

Zachary T Morrow, John-Demian Sauer.

  Listeria monocytogenes is a facultative intracellular pathogen that has been used for decades to understand mechanisms of bacterial pathogenesis and both innate and adaptive immunity. L. monocytogenes is a potent activator of CD8+ T-cell-mediated immunity, yet how the innate immune response to infection modulates CD8+ T-cell responses is incompletely understood. Here, we address how two innate immune pathways triggered by L. monocytogenes, type I interferon (IFN) production and inflammasome activation, impact the CD8+ T-cell response. We utilized a combination of mutant mice and genetically engineered L. monocytogenes to address this question. Mice lacking the type I IFN receptor (IFNAR-/-) had the most robust T-cell response, while caspase-1-/- mice were not different from wild type (WT). Caspase-1-/-/IFNAR-/- mice had fewer T-cells than IFNAR-/- mice, suggesting a role for inflammasome activation in the absence of type I IFN. IFNAR-/- had more than twice as many memory precursors promoting enhanced protection from rechallenge. Importantly, short-lived effectors were equivalent in all strains of mice. L. monocytogenes strains genetically modified to induce lower type I interferon production yielded enhanced T-cell responses. IFNAR-/- dendritic cells induced more T-cells to proliferate than WT in ex vivo T-cell proliferation assays, suggesting deficits from type I interferon signaling may be dendritic cell intrinsic, rather than acting on T-cells. Thus, modulating type I IFN signaling during vaccination may lead to more potent T-cell-based vaccines. Importantly, this suggests innate immune signaling significantly impacts the CD8+ T-cell response and suggests CD8+ T-cell quantity and quality are important factors to consider during rational vaccine design.

Keywords:  Listeria monocytogenes; antigen-presenting cell; inflammasome; interferon; type I interferon; vaccine

DOI:  https://doi.org/10.1128/iai.00540-22
Am J Physiol Cell Physiol. 2023 Jun 12.

Moderate exercise induces trained immunity in macrophages.

Mayoorey Murugathasan, Ardavan Jafari, Amandeep Amandeep, Syed A Hassan, Matthew Chihata, Ali A Abdul-Sater.

  Despite its importance in protecting the host from infections and injury, excessive inflammation may lead to serious human diseases including autoimmune disorders, cardiovascular diseases, diabetes, and cancer. Exercise is a known immunomodulator; however, whether exercise causes long term changes in inflammatory responses and how these changes occur are lacking. Here, we show that chronic moderate intensity training of mice leads to persistent metabolic rewiring and changes to chromatin accessibility in bone marrow derived macrophages (BMDMs), which, in turn, tempers their inflammatory responses. We show that BMDMs from exercised mice exhibited a decrease in lipopolysaccharide (LPS) induced NF-kB activation and pro-inflammatory gene expression along with an increase in M2-like associated genes when compared to BMDMs from sedentary mice. This was associated with improved mitochondrial quality and increased reliance on oxidative phosphorylation accompanied with reduced mitochondrial ROS production. Mechanistically, ATAC-seq analysis showed changes in chromatin accessibility of genes associated with inflammatory and metabolic pathways. Overall, our data suggest that chronic moderate exercise can influence the inflammatory responses of macrophages by reprogramming their metabolic and epigenetic landscape.

Keywords:  Exercise; Inflammation; Macrophages; Mitochondria; epigenetic

DOI:  https://doi.org/10.1152/ajpcell.00130.2023
Immunity. 2023 Jun 13. pii: S1074-7613(23)00218-2. [Epub ahead of print]56(6): 1168-1186

Regulation of systemic metabolism by tissue-resident immune cell circuits.

Joey H Li, Matthew R Hepworth, Timothy E O'Sullivan.

  Recent studies have demonstrated that tissue homeostasis and metabolic function are dependent on distinct tissue-resident immune cells that form functional cell circuits with structural cells. Within these cell circuits, immune cells integrate cues from dietary contents and commensal microbes in addition to endocrine and neuronal signals present in the tissue microenvironment to regulate structural cell metabolism. These tissue-resident immune circuits can become dysregulated during inflammation and dietary overnutrition, contributing to metabolic diseases. Here, we review the evidence describing key cellular networks within and between the liver, gastrointestinal tract, and adipose tissue that control systemic metabolism and how these cell circuits become dysregulated during certain metabolic diseases. We also identify open questions in the field that have the potential to enhance our understanding of metabolic health and disease.

Keywords:  cell circuits; immunometabolism; metabolism; systems immunology; tissue homeostasis; tissue-resident

DOI:  https://doi.org/10.1016/j.immuni.2023.05.001
Sci Immunol. 2023 Jun 23. 8(84): eadc9081

Activation of regulatory dendritic cells by Mertk coincides with a temporal wave of apoptosis in neonatal lungs.

Aaron Silva-Sanchez, Selene Meza-Perez, Mingyong Liu, Sara L Stone, Leopoldo Flores-Romo, Eric Ubil, Frances E Lund, Alexander F Rosenberg, Troy D Randall.

Multiple mechanisms restrain inflammation in neonates, most likely to prevent tissue damage caused by overly robust immune responses against newly encountered pathogens. Here, we identify a population of pulmonary dendritic cells (DCs) that express intermediate levels of CD103 (CD103int) and appear in the lungs and lung-draining lymph nodes of mice between birth and 2 weeks of age. CD103int DCs express XCR1 and CD205 and require expression of the transcription factor BATF3 for development, suggesting that they belong to the cDC1 lineage. In addition, CD103int DCs express CCR7 constitutively and spontaneously migrate to the lung-draining lymph node, where they promote stromal cell maturation and lymph node expansion. CD103int DCs mature independently of microbial exposure and TRIF- or MyD88-dependent signaling and are transcriptionally related to efferocytic and tolerogenic DCs as well as mature, regulatory DCs. Correlating with this, CD103int DCs show limited ability to stimulate proliferation and IFN-γ production by CD8+ T cells. Moreover, CD103int DCs acquire apoptotic cells efficiently, in a process that is dependent on the expression of the TAM receptor, Mertk, which drives their homeostatic maturation. The appearance of CD103int DCs coincides with a temporal wave of apoptosis in developing lungs and explains, in part, dampened pulmonary immunity in neonatal mice. Together, these data suggest a mechanism by which DCs sense apoptotic cells at sites of noninflammatory tissue remodeling, such as tumors or the developing lungs, and limit local T cell responses.

DOI: https://doi.org/10.1126/sciimmunol.adc9081
J Biol Chem. 2023 Jun 13. pii: S0021-9258(23)01950-6. [Epub ahead of print] 104922

A role for fibroblast-derived SASP factors in the activation of pyroptotic cell death in mammary epithelial cells.

Lisa M Hom, Seunghoon Sun, Jamie Campbell, Pinyan Liu, Shannon Culbert, Ireland M Murphy, Zachary T Schafer.

  In normal tissue homeostasis, bidirectional communication between different cell types can shape numerous biological outcomes.Many studies have documented instances of reciprocal communication between fibroblasts and cancer cells that functionally change cancer cell behavior. However, less is known about how these heterotypic interactions shape epithelial cell function in the absence of oncogenic transformation. Furthermore, fibroblasts are prone to undergo senescence, which is typified by an irreversible cell cycle arrest. Senescent fibroblasts are also known to secrete various cytokines into the extracellular space; a phenomenon that is termed the senescence-associated secretory phenotype (SASP). While the role of fibroblast derived SASP factors on cancer cells has been well studied, the impact of these factors on normal epithelial cells remains poorly understood. We discovered that treatment of normal mammary epithelial cells with conditioned media (CM) from senescent fibroblasts (SASP CM) results in a caspase-dependent cell death. This capacity of SASP CM to cause cell death is maintained across multiple senescence-inducing stimuli. However, the activation of oncogenic signaling in mammary epithelial cells mitigates the ability of SASP CM to induce cell death. Despite the reliance of this cell death on caspase activation, we discovered that SASP CM does not cause cell death by the extrinsic or intrinsic apoptotic pathway. Instead, these cells die by an NLRP3, caspase-1, and gasdermin D (GSDMD)-dependent induction of pyroptosis. Taken together, our findings reveal that senescent fibroblasts can cause pyroptosis in neighboring mammary epithelial cells, which has implications for therapeutic strategies that perturb the behavior of senescent cells.

Keywords:  SASP; caspase 1; cell death; epithelial cell; fibroblast; gasdermin D; pyroptosis; senescence

DOI:  https://doi.org/10.1016/j.jbc.2023.104922
STAR Protoc. 2023 Jun 12. pii: S2666-1667(23)00304-0. [Epub ahead of print]4(3): 102337

Protocol for generating airway organoids from 2D air liquid interface-differentiated nasal epithelia for use in a functional CFTR assay.

Lisa W Rodenburg, Isabelle S van der Windt, Henriette H M Dreyer, Shannon M A Smits, Loes A den Hertog-Oosterhoff, Ellen M Aarts, Jeffrey M Beekman, Gimano D Amatngalim.

  We present a protocol to generate organoids from air-liquid-interface (ALI)-differentiated nasal epithelia. We detail their application as cystic fibrosis (CF) disease model in the cystic fibrosis transmembrane conductance regulator (CFTR)-dependent forskolin-induced swelling (FIS) assay. We describe steps for isolation, expansion and cryostorage of nasal brushing-derived basal progenitor cells, and their differentiation in ALI cultures. Furthermore, we detail the conversion of differentiated epithelial fragments into organoids of healthy controls and CF subjects for validating CFTR function and modulator responses. For complete details on the use and execution of this protocol, please refer to Amatngalim et al.1.

Keywords:  Cell culture; Organoids

DOI:  https://doi.org/10.1016/j.xpro.2023.102337
Front Allergy. 2023 ;4 1120999

The role of the respiratory microbiome in asthma.

Christina D Campbell, Margaret Gleeson, Imran Sulaiman.

  Asthma is a common airways disease and the human microbiome plays an increasingly recognised role in asthma pathogenesis. Furthermore, the respiratory microbiome varies with asthma phenotype, endotype and disease severity. Consequently, asthma therapies have a direct effect on the respiratory microbiome. Newer biological therapies have led to a significant paradigm shift in how we treat refractory Type 2 high asthma. While airway inflammation is the generally accepted mechanism of action of all asthma therapies, including both inhaled and systemic therapies, there is evidence to suggest that they may also alter the microbiome to create a more functionally balanced airway microenvironment while also influencing airway inflammation directly. This downregulated inflammatory cascade seen biochemically, and reflected in improved clinical outcomes, supports the hypothesis that biological therapies may in fact affect the microbiome-host immune system dynamic and thus represent a therapeutic target for exacerbations and disease control.

Keywords:  asthma; biologic therapy; childhood asthma; microbiome; respiratory microbiome

DOI:  https://doi.org/10.3389/falgy.2023.1120999
Microorganisms. 2023 Apr 28. pii: 1148. [Epub ahead of print]11(5):

Oral Administration of Lacticaseibacillus rhamnosus CRL1505 Modulates Lung Innate Immune Response against Klebsiella pneumoniae ST25.

Stefania Dentice Maidana, Yoshiya Imamura, Mariano Elean, Leonardo Albarracín, Keita Nishiyama, Yoshihito Suda, Shoichiro Kurata, María Ángela Jure, Haruki Kitazawa, Julio Villena.

  Orally administered Lacticaseibacillus rhamnosus CRL1505 enhances respiratory immunity, providing protection against respiratory viruses and Streptococcus pneumoniae. However, the capacity of the CRL1505 strain to improve respiratory immunity against Gram-negative bacterial infections has not been evaluated before. The aim of this work was to evaluate whether the Lcb. rhamnosus CRL1505 was able to beneficially regulate the respiratory innate immune response and enhance the resistance to hypermucoviscous KPC-2-producing Klebsiella pneumoniae of the sequence type 25 (ST25). BALB/c mice were treated with the CRL1505 strain via the oral route and then nasally challenged with K. pneumoniae ST25 strains LABACER 01 or LABACER 27. Bacterial cell counts, lung injuries and the respiratory and systemic innate immune responses were evaluated after the bacterial infection. The results showed that K. pneumoniae ST25 strains increased the levels of TNF-α, IL-1β, IL-6, IFN-γ, IL-17, KC and MPC-1 in the respiratory tract and blood, as well as the numbers of BAL neutrophils and macrophages. Mice treated with Lcb. rhamnosus CRL1505 had significantly lower K. pneumoniae counts in their lungs, as well as reduced levels of inflammatory cells, cytokines and chemokines in the respiratory tract and blood when compared to infected controls. Furthermore, higher levels of the regulatory cytokines IL-10 and IL-27 were found in the respiratory tract and blood of CRL1505-treated mice than controls. These results suggest that the ability of Lcb. rhamnosus CRL1505 to help with the control of detrimental inflammation in lungs during K. pneumoniae infection would be a key feature to improve the resistance to this pathogen. Although further mechanistic studies are necessary, Lcb. rhamnosus CRL1505 can be proposed as a candidate to improve patients' protection against hypermucoviscous KPC-2-producing strains belonging to the ST25, which is endemic in the hospitals of our region.

Keywords:  K. pneumoniae; Lcb. rhamnosus CRL1505; innate immunity; probiotics

DOI:  https://doi.org/10.3390/microorganisms11051148
Front Immunol. 2023 ;14 1219083

Editorial: Insights in microbial immunology: 2022.

Ian Marriott, Imtiaz A Khan, Ulrich E Schaible.



Keywords:  achievements and challenges; infection immunology; microbial immunology; microbiota; multi-omic analyses; state-of the art review

DOI:  https://doi.org/10.3389/fimmu.2023.1219083
Front Bioeng Biotechnol. 2023 ;11 1191104

Integration of immune cells in organs-on-chips: a tutorial.

Lisette Van Os, Britta Engelhardt, Olivier T Guenat.

  Viral and bacterial infections continue to pose significant challenges for numerous individuals globally. To develop novel therapies to combat infections, more insight into the actions of the human innate and adaptive immune system during infection is necessary. Human in vitro models, such as organs-on-chip (OOC) models, have proven to be a valuable addition to the tissue modeling toolbox. The incorporation of an immune component is needed to bring OOC models to the next level and enable them to mimic complex biological responses. The immune system affects many (patho)physiological processes in the human body, such as those taking place during an infection. This tutorial review introduces the reader to the building blocks of an OOC model of acute infection to investigate recruitment of circulating immune cells into the infected tissue. The multi-step extravasation cascade in vivo is described, followed by an in-depth guide on how to model this process on a chip. Next to chip design, creation of a chemotactic gradient and incorporation of endothelial, epithelial, and immune cells, the review focuses on the hydrogel extracellular matrix (ECM) to accurately model the interstitial space through which extravasated immune cells migrate towards the site of infection. Overall, this tutorial review is a practical guide for developing an OOC model of immune cell migration from the blood into the interstitial space during infection.

Keywords:  chemoattractant; endothelium; hydrogel ECM; immune cells; infection; infection-on-chip; inflammation; organ-on-chip

DOI:  https://doi.org/10.3389/fbioe.2023.1191104
FEBS J. 2023 Jun 10.

Interleukin-1 family cytokines at the crossroads of microbiome regulation in barrier health and disease.

Paloma Narros Fernández, Shrikanth Chomanahalli Basavarajappa, Patrick T Walsh.

  Recent advances in understanding how the microbiome can influence both the physiology and the pathogenesis of disease in humans have highlighted the importance of gaining a deeper insight into the complexities of the host-microbial dialogue. In tandem with this progress, has been a greater understanding of the biological pathways which regulate both homeostasis and inflammation at barrier tissue sites, such as the skin and the gut. In this regard, the Interleukin-1 family of cytokines, which can be segregated into IL-1, IL-18 and IL-36 subfamilies, have emerged as important custodians of barrier health and immunity. With established roles as orchestrators of various inflammatory diseases in both the skin and intestine, it is now becoming clear that IL-1 family cytokine activity is not only directly influenced by external microbes, but can also play important roles in shaping the composition of the microbiome at barrier sites. This review explores the current knowledge surrounding the evidence that places these cytokines as key mediators at the interface between the microbiome and human health and disease at the skin and intestinal barrier tissues.

Keywords:  Interleukin-1 family; cytokines; gut; microbiome; skin

DOI:  https://doi.org/10.1111/febs.16888
Microbiol Spectr. 2023 Jun 15. e0524722

Altered Respiratory Microbiomes, Plasma Metabolites, and Immune Responses in Influenza A Virus and Methicillin-Resistant Staphylococcus aureus Coinfection.

Qichao Chen, Manjiao Liu, Hao Guo, Kaiying Wang, Jiangfeng Liu, Yun Wang, Yanfeng Lin, Jinhui Li, Peihan Li, Lang Yang, Leili Jia, Juntao Yang, Peng Li, Hongbin Song.

  Influenza A virus (IAV)-methicillin-resistant Staphylococcus aureus (MRSA) coinfection causes severe respiratory infections. The host microbiome plays an important role in respiratory tract infections. However, the relationships among the immune responses, metabolic characteristics, and respiratory microbial characteristics of IAV-MRSA coinfection have not been fully studied. We used specific-pathogen-free (SPF) C57BL/6N mice infected with IAV and MRSA to build a nonlethal model of IAV-MRSA coinfection and characterized the upper respiratory tract (URT) and lower respiratory tract (LRT) microbiomes at 4 and 13 days postinfection by full-length 16S rRNA gene sequencing. Immune response and plasma metabolism profile analyses were performed at 4 days postinfection by flow cytometry and liquid chromatography-tandem mass spectrometry (LC-MS/MS). The relationships among the LRT microbiota, the immune response, and the plasma metabolism profile were analyzed by Spearman's correlation analysis. IAV-MRSA coinfection showed significant weight loss and lung injury and significantly increased loads of IAV and MRSA in bronchoalveolar lavage fluid (BALF). Microbiome data showed that coinfection significantly increased the relative abundances of Enterococcus faecalis, Enterobacter hormaechei, Citrobacter freundii, and Klebsiella pneumoniae and decreased the relative abundances of Lactobacillus reuteri and Lactobacillus murinus. The percentages of CD4+/CD8+ T cells and B cells in the spleen; the levels of interleukin-9 (IL-9), interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), IL-6, and IL-8 in the lung; and the level of mevalonolactone in plasma were increased in IAV-MRSA-coinfected mice. L. murinus was positively correlated with lung macrophages and natural killer (NK) cells, negatively correlated with spleen B cells and CD4+/CD8+ T cells, and correlated with multiple plasma metabolites. Future research is needed to clarify whether L. murinus mediates or alters the severity of IAV-MRSA coinfection. IMPORTANCE The respiratory microbiome plays an important role in respiratory tract infections. In this study, we characterized the URT and LRT microbiota, the host immune response, and plasma metabolic profiles during IAV-MRSA coinfection and evaluated their correlations. We observed that IAV-MRSA coinfection induced severe lung injury and dysregulated host immunity and plasma metabolic profiles, as evidenced by the aggravation of lung pathological damage, the reduction of innate immune cells, the strong adaptation of the immune response, and the upregulation of mevalonolactone in plasma. L. murinus was strongly correlated with immune cells and plasma metabolites. Our findings contribute to a better understanding of the role of the host microbiome in respiratory tract infections and identified a key bacterial species, L. murinus, that may provide important references for the development of probiotic therapies.

Keywords:  IAV-MRSA coinfection; Lactobacillus murinus; adaptive immunity; bacterial-viral coinfection; host immunity; innate immunity; plasma metabolites; respiratory microbiomes

DOI:  https://doi.org/10.1128/spectrum.05247-22