bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2023‒02‒19
25 papers selected by
Chun-Chi Chang
University Hospital Zurich

  1. Eur J Immunol. 2023 Feb 13. e2250235
      Regulated cell death (RCD) triggered by innate immune activation is an important strategy for host survival during pathogen invasion and perturbations of cellular homeostasis. There are two main categories of RCD, including non-lytic and lytic pathways. Apoptosis is the most well-characterized non-lytic RCD, and the inflammatory pyroptosis and necroptosis pathways are among the best known lytic forms. While these were historically viewed as independent RCD pathways, extensive evidence of crosstalk among their molecular components created a knowledge gap in our mechanistic understanding of RCD and innate immune pathway components, which led to the identification of PANoptosis. PANoptosis is a unique innate immune inflammatory RCD pathway that is regulated by PANoptosome complexes upon sensing pathogens, pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) or the cytokines produced downstream. Cytosolic innate immune sensors, such as ZBP1, AIM2 and RIPK1, promote the assembly of PANoptosomes to drive PANoptosis. In this review, we discuss the molecular components of the known PANoptosomes and highlight the mechanisms of PANoptosome assembly, activation and regulation identified to date. We also discuss how PANoptosomes and mutations in PANoptosome components are linked to diseases. Given the impact of RCD, and PANoptosis specifically, across the disease spectrum, improved understanding of PANoptosomes and their regulation will be critical for identifying new therapeutic targets and strategies. This article is protected by copyright. All rights reserved.
    Keywords:  apoptosis; caspases; inflammasome; necroptosis; pyroptosis
  2. Cardiovasc Res. 2023 Feb 16. pii: cvad030. [Epub ahead of print]
      Low-grade systemic inflammation is a key pathophysiological component of atherosclerotic cardiovascular disease (CVD), and long-term activation of myeloid cells is thought to be crucial for these effects. Obesity and associated metabolic complications including hyperglycaemia and dyslipoproteinaemia can induce long-lasting inflammatory reprogramming of the innate immune cells and their bone marrow progenitors, which in turn contributes to atherosclerosis. In this review, we discuss the mechanisms through which innate immune cells undergo long-term changes in their functional, epigenetic, and metabolic characteristics upon even short-term exposure to endogenous ligands, a process also termed 'trained immunity'. Inappropriate induction of trained immunity leads to the development of long-lasting hyperinflammatory and proatherogenic changes in monocytes and macrophages, an important factor in the development of atherosclerosis and CVDs. Knowledge of the specific immune cells and the distinct intracellular molecular pathways involved in the induction of trained immunity will reveal novel pharmacological targets that could be used to prevent or treat CVDs in the future.
    Keywords:  Atherosclerosis; Inflammation; Monocytes; Obesity; Trained immunity
  3. medRxiv. 2023 Feb 06. pii: 2023.02.02.23285247. [Epub ahead of print]
      Leishmania braziliensis infection results in inflammation and skin injury, with highly variable and unpredictable clinical outcomes. Here, we investigated the potential impact of microbiota on infection-induced inflammatory responses and disease resolution by conducting an integrated analysis of the skin microbiome and host transcriptome on a cohort of 62 L. braziliensis -infected patients. We found that overall bacterial burden and microbiome configurations dominated with Staphylococcus spp. were associated with delayed healing and enhanced inflammatory responses, especially by IL-1 family members. Dual RNA-seq of human lesions revealed that high lesional S. aureus transcript abundance was associated with delayed healing and increased expression of IL-1β. This cytokine was critical for modulating disease outcome in L. braziliensis -infected mice colonized with S. aureus , as its neutralization reduced pathology and inflammation. These results implicate the microbiome in cutaneous leishmaniasis disease outcomes in humans and suggest host-directed therapies to mitigate the inflammatory consequences.
  4. Front Cell Infect Microbiol. 2023 ;13 1141131
    Keywords:  epithelia cells; host defense; microbiota; mucosal; pathogens
  5. Eur J Immunol. 2023 Feb 13. e2250106
      Over the last years, technological advances in the field of asthma have led to the identification of two disease endotypes, namely type 2-high and type 2-low asthma, characterized by different pathophysiologic mechanisms at a cellular and molecular level. Although specific immune cells are important contributors to each of the recognized asthma endotype, the lung epithelium is now regarded as a crucial player able to orchestrate responses to inhaled environmental triggers such as allergens and microbes. The impact of the epithelium goes beyond its physical barrier. It is nowadays considered as a part of the innate immune system that can actively respond to insults. Activated epithelial cells, by producing a specific set of cytokines, trigger innate and adaptive immune cells to cause pathology. Here, we review how the epithelium contributes to the development of Th2 sensitization to allergens and asthma with a "type 2-high" signature, in both murine models and human studies of this asthma endotype. We also discuss epithelial responses to respiratory viruses, like RV, RSV and SARS-CoV-2, and how these triggers influence not only asthma development but also asthma exacerbation. Finally, we also summarize the results of promising clinical trials using biologicals targeting epithelial-derived cytokines in asthmatic patients. This article is protected by copyright. All rights reserved.
    Keywords:  Asthma; Epithelial cells; Microbiome; SARS-CoV-2; Th2
  6. Front Immunol. 2023 ;14 1111298
      Respiratory mucosal surfaces are continuously exposed to not only innocuous non-self antigens but also pathogen-associated molecular patterns (PAMPs) originating from environmental or symbiotic microbes. According to either "self/non-self" or "danger" models, this should systematically result in homeostasis breakdown and the development of immune responses directed to inhaled harmless antigens, such as T helper type (Th)2-mediated asthmatic reactions, which is fortunately not the case in most people. This discrepancy implies the existence, in the lung, of regulatory mechanisms that tightly control immune homeostasis. Although such mechanisms have been poorly investigated in comparison to the ones that trigger immune responses, a better understanding of them could be useful in the development of new therapeutic strategies against lung diseases (e.g., asthma). Here, we review current knowledge on innate immune cells that prevent the development of aberrant immune responses in the lung, thereby contributing to mucosal homeostasis.
    Keywords:  airway allergy; homeostasis; immunoregulation; innate immunity; lung
  7. Autophagy. 2023 Feb 13.
      Previously considered as an exclusive extracellular bacterium, Staphylococcus aureus has been shown to be able to invade many cells in vitro and in humans. Once inside the host cell, both cytosolic and endosome-associated S. aureus strongly induce macroautophagy/autophagy. Whether autophagy fosters S. aureus intracellular survival or clearance remains unclear. The YAP1-TEAD axis regulates the expression of target genes controlling the cell fate (e.g., proliferation, migration, cell cycle …). Growing evidence indicates that YAP1-TEAD also regulates autophagy and lysosomal pathways. Recently we showed that the YAP1-TEAD axis promotes autophagy and lysosome biogenesis to restrict S. aureus intracellular replication. We also discovered that the C3 exoenzyme-like EDIN-B toxin produced by the pathogenic S. aureus ST80 strain inhibits YAP1 nuclear translocation resulting in a strong increase of intracellular S. aureus burden.
    Keywords:  Autophagy; C3 exoenzyme; EDIN; Staphylococcus aureus; YAP; cell-autonomous immunity; host response genes; inflammation; lysosome
  8. J Virol. 2023 Feb 13. e0176422
      Respiratory syncytial virus (RSV) infects more than 60% of infants in their first year of life. Since an experimental formalin-inactivated (FI) RSV vaccine tested in the 1960s caused enhanced respiratory disease (ERD), few attempts have been made to vaccinate infants. ERD is characterized by Th2-biased responses, lung inflammation, and poor protective immune memory. Innate immune memory displays an increased nonspecific effector function upon restimulation, a process called trained immunity, or a repressed effector function upon restimulation, a process called tolerance, which participates in host defense and inflammatory disease. Mycobacterium bovis bacillus Calmette-Guérin (BCG) given at birth can induce trained immunity as well as heterologous Th1 responses. We speculate that BCG given at birth followed by FI-RSV may alleviate ERD and enhance protection through promoting trained immunity and balanced Th immune memory. Neonatal mice were given BCG at birth and then vaccinated with FI-RSV+Al(OH)3. BCG/FI-RSV+Al(OH)3 induced trained macrophages, tissue-resident memory T cells (TRM), and specific cytotoxic T lymphocytes (CTL) in lungs and inhibited Th2 and Th17 cell immune memory, all of which contributed to inhibition of ERD and increased protection. Notably, FI-RSV+Al(OH)3 induced tolerant macrophages, while BCG/FI-RSV+Al(OH)3 prevented the innate tolerance through promoting trained macrophages. Moreover, inhibition of ERD was attributed to trained macrophages or TRM in lungs but not memory T cells in spleens. Therefore, BCG given at birth to regulate trained immunity and TRM may be a new strategy for developing safe and effective RSV killed vaccines for young infants. IMPORTANCE RSV is the leading cause of severe lower respiratory tract infection of infants. ERD, characterized by Th2-biased responses, inflammation, and poor immune memory, has been an obstacle to the development of safe and effective killed RSV vaccines. Innate immune memory participates in host defense and inflammatory disease. BCG given at birth can induce trained immunity as well as heterologous Th1 responses. Our results showed that BCG/FI-RSV+Al(OH)3 induced trained macrophages, TRM, specific CTL, and balanced Th cell immune memory, which contributed to inhibition of ERD and increased protection. Notably, FI-RSV+Al(OH)3 induced tolerant macrophages, while BCG/FI-RSV+Al(OH)3 prevented tolerance through promoting trained macrophages. Moreover, inhibition of ERD was attributed to trained macrophages or TRM in lungs but not memory T cells in spleens. BCG at birth as an adjuvant to regulate trained immunity and TRM may be a new strategy for developing safe and effective RSV killed vaccines for young infants.
    Keywords:  FI-RSV vaccine-enhanced respiratory disease (ERD); bacillus Calmette-Guérin (BCG); innate immune memory; tissue-resident memory T cells; trained macrophages
  9. bioRxiv. 2023 Feb 03. pii: 2023.02.02.523770. [Epub ahead of print]
      Canonically, complement is a serum-based host defense system that protects against systemic microbial invasion. Little is known about the production and function of complement components on mucosal surfaces. Here we show gut complement component 3 (C3), central to complement function, is regulated by the composition of the microbiota in healthy humans and mice, leading to host-specific gut C3 levels. Stromal cells in intestinal lymphoid follicles (LFs) are the predominant source of intestinal C3. During enteric infection with Citrobacter rodentium or enterohemorrhagic Escherichia coli, luminal C3 levels increase significantly and are required for protection. C. rodentium is remarkably more invasive to the gut epithelium of C3-deficient mice than of wild-type mice. In the gut, C3-mediated phagocytosis of C. rodentium functions to clear pathogens. Our study reveals that variations in gut microbiota determine individuals’ intestinal mucosal C3 levels, dominantly produced by LF stromal cells, which directly correlate with protection against enteric infection.Highlights: Gut complement component 3 (C3) is induced by the microbiome in healthy humans and mice at a microbiota-specific level.Gut stromal cells located in intestinal lymphoid follicles are a major source of luminal C3 During enteric infections with Citrobacter rodentium or enterohemorrhagic Escherichia coli, gut luminal C3 levels increase and are required for protection. C. rodentium is significantly more invasive of the gut epithelium in C3-deficient mice when compared to WT mice. In the gut, C3-mediated opsonophagocytosis of C. rodentium functions to clear pathogens.
  10. Am J Respir Crit Care Med. 2023 Feb 15.
      RATIONALE: The resolution of inflammation is an active process coordinated by mediators and immune cells to restore tissue homeostasis. However, the mechanisms for resolving eosinophilic allergic lung inflammation triggered by inhaled allergens have not been fully elucidated.OBJECTIVES: Our objectives were to investigate the cellular mechanism of tissue-resident macrophages involved in the resolution process of eosinophilic lung inflammation.
    METHODS: For the study, we utilized the IRB-approved protocol for human subsegmental bronchoprovocation with allergen (SBP-AG), mouse models for allergic lung inflammation, and novel transgenic mice, including a conditional CCL26 knockout. The samples were analyzed using mass cytometry, sc-RNA-sequencing, biophysical, and immunological analyses.
    RESULTS: We compared alveolar macrophage (AM) subsets in the BAL before and after allergen provocation. In response to provocation with inhaled allergens, the subsets of AMs are dynamically changed in humans and mice. In the steady state, the AM subset expressing CX3CR1 is a relatively small fraction in bronchoalveolar space and lung tissue but drastically increases after allergen challenges. This subset presents unique patterns of gene expression compared to classical AM, expressing high C1q family genes. CX3CR1+ macrophages are activated by airway epithelial cells derived-CCL26 via a receptor-ligand interaction. The binding of CCL26 to the CX3CR1+ receptor induces CX3CR1+ macrophages to secrete C1q, subsequently facilitating the clearance of eosinophils. Furthermore, the depletion of CX3CR1 macrophages or CCL26 in airway epithelial cells delays the resolution of allergic lung inflammation displaying prolonged tissue eosinophilia.
    CONCLUSION: These findings indicate that the CCL26-CX3CR1 pathway is pivotal in resolving eosinophilic allergic lung inflammation.
    Keywords:  C1q; CCL26; CX3CR1 macrophage; Inflammation resolution
  11. bioRxiv. 2023 Jan 30. pii: 2023.01.29.526157. [Epub ahead of print]
      Background: Streptococcus pneumoniae (Spn) is typically an asymptomatic colonizer of the nasopharynx but it also causes pneumonia and disseminated disease affecting various host anatomical sites. Transition from colonization to invasive disease is not well understood. Studies have shown that such a transition can occur as result of influenza A virus coinfection.Methods: We investigated the pneumococcal (serotype 19F, strain EF3030) and host transcriptomes with and without influenza A virus (A/California/07 2009 pH1N1) infection at this transition. This was done using primary, differentiated Human Bronchial Epithelial Cells (nHBEC) in a transwell monolayer model at an Air-Liquid Interface (ALI), with multispecies deep RNA-seq.
    Results: Distinct pneumococcal gene expression profiles were observed in the presence and absence of influenza. Influenza coinfection allowed for significantly greater pneumococcal growth and triggered the differential expression of bacterial genes corresponding to multiple metabolic pathways; in totality suggesting a fundamentally altered bacterial metabolic state and greater nutrient availability when coinfecting with influenza. Surprisingly, nHBEC transcriptomes were only modestly perturbed by infection with EF3030 alone in comparison to that resulting from Influenza A infection or coinfection, which had drastic alterations in thousands of genes. Influenza infected host transcriptomes suggest significant loss of ciliary function in host nHBEC cells.
    Conclusions: Influenza A virus infection of nHBEC promotes pneumococcal infection. One reason for this is an altered metabolic state by the bacterium, presumably due to host components made available as result of viral infection. Influenza infection had a far greater impact on the host response than did bacterial infection alone, and this included down regulation of genes involved in expressing cilia. We conclude that influenza infection promotes a pneumococcal metabolic shift allowing for transition from colonization to disseminated disease.
    Author summary: Secondary Streptococcus pneumoniae bacterial infections typically occur after influenza A virus respiratory infection. Such coinfections often lead to invasive pneumococcal disease. The mechanisms involved in this process are not well understood. Here, using an ex vivo human lung bronchial epithelial cell model, we investigated the biological processes of the host and pneumococcus occurring at this niche, during coinfection with multi-species transcriptomics techniques, and in vivo mouse model experimentation. We observed stark differences in global pneumococcal metabolism in different infection states, as well as viral induced epithelial cell changes in ciliary function, potentially aiding pneumococcal dissemination. Overall, this study identified broad and targeted biological processes involved in this host-pathogen interaction.
  12. Ecotoxicol Environ Saf. 2023 Feb 10. pii: S0147-6513(23)00141-0. [Epub ahead of print]252 114637
      Fungal contamination is omnipresent, and inhalation of fungi-contaminated organic dust leads to hypersensitivity pneumonitis (HP), in which neutrophils played a pivotal role. Existing studies have suggested that cell homeostasis is crucial for the pathogenesis of the inflammatory disease. Although HMGB1 has been shown to contribute to suppressing HP, there is a lack of studies on its mechanisms, especially the regulation of neutrophil homeostasis. This study aims to investigate how HMGB1 regulates neutrophil function by affecting neutrophil homeostasis, and then affects lung inflammation induced by β-glucan, the exposure marker of fungi. Our results showed that deficient HMGB1 led to neutrophil death by disrupting the balance between autophagy and pyroptosis after β-glucan treatment. And HMGB1 deficiency exacerbated the β-glucan-induced lung inflammation and neutrophil dysfunction both in vivo and in vitro. Furthermore, HMGB1 contributed to remodeling neutrophil function by restricting autophagy and aggravating pyroptosis β-glucan exposure. Our funding suggested that HMGB1 deficiency could break the balance between autophagy and pyroptosis towards pyroptosis to cause neutrophil dysfunction during the exacerbated inflammatory response, which provides insights into the pathogenesis of HP and the potential biological targets for its treatment. DATA AVAILABILITY: The datasets used during the current study are available from the corresponding author on reasonable request.
    Keywords:  Autophagy; Fungi contamination; Hypersensitivity pneumonitis; Neutrophil; Pyroptosis; β-glucan
  13. Nat Commun. 2023 Feb 13. 14(1): 721
      Epithelial tissues provide front-line barriers shielding the organism from invading pathogens and harmful substances. In the airway epithelium, the combined action of multiciliated and secretory cells sustains the mucociliary escalator required for clearance of microbes and particles from the airways. Defects in components of mucociliary clearance or barrier integrity are associated with recurring infections and chronic inflammation. The timely and balanced differentiation of basal cells into mature epithelial cell subsets is therefore tightly controlled. While different growth factors regulating progenitor cell proliferation have been described, little is known about the role of metabolism in these regenerative processes. Here we show that basal cell differentiation correlates with a shift in cellular metabolism from glycolysis to fatty acid oxidation (FAO). We demonstrate both in vitro and in vivo that pharmacological and genetic impairment of FAO blocks the development of fully differentiated airway epithelial cells, compromising the repair of airway epithelia. Mechanistically, FAO links to the hexosamine biosynthesis pathway to support protein glycosylation in airway epithelial cells. Our findings unveil the metabolic network underpinning the differentiation of airway epithelia and identify novel targets for intervention to promote lung repair.
  14. Sci Transl Med. 2023 Feb 15. 15(683): eabj3289
      Innate immunity not only shapes the way epithelial barriers interpret environmental cues but also drives adaptive responses. Therefore, modulators of innate immune responses are expected to have high therapeutic potential across immune-mediated inflammatory diseases. IRAK4 is a kinase that integrates signaling downstream of receptors acting at the interface between innate and adaptive immune responses, such as Toll-like receptors (TLRs), interleukin-1R (IL-1R), and IL-18R. Because effects of IRAK4 inhibition are stimulus, cell type, and species dependent, the evaluation of the therapeutic potential of IRAK4 inhibitors requires a highly translational approach. Here, we profiled a selective IRAK4 inhibitor, GLPG2534, in an extensive panel of models of inflammatory skin diseases, translationally expanding evidence from in vitro to in vivo and from mouse to human. In vitro, IRAK4 inhibition resulted in substantial inhibition of TLR and IL-1 responses in dendritic cells, keratinocytes, granulocytes, and T cells but only weakly affected dermal fibroblast responses. Furthermore, disease activity in murine models of skin inflammation (IL-23-, IL-33-, imiquimod-, and MC903-induced) was markedly dampened by IRAK4 inhibition. Last, inhibiting IRAK4 reversed pathogenic molecular signatures in human lesional psoriasis and atopic dermatitis biopsies. Over the variety of models used, IRAK4 inhibition consistently affected central mediators of psoriasis (IL-17A) and atopic dermatitis (IL-4 and IL-13). Overall, our data highlight IRAK4 as a central player in skin inflammatory processes and demonstrate the potential of IRAK4 inhibition as a therapeutic strategy in chronic inflammatory skin diseases.
  15. Front Immunol. 2022 ;13 1044592
      Pulmonary macrophages have two distinct ontogenies: long-lived embryonically-seeded alveolar macrophages (AM) and bone marrow-derived macrophages (BMDM). Here, we show that after infection with a virulent strain of Mycobacterium tuberculosis (H37Rv), primary murine AM exhibit a unique transcriptomic signature characterized by metabolic reprogramming distinct from conventional BMDM. In contrast to BMDM, AM failed to shift from oxidative phosphorylation (OXPHOS) to glycolysis and consequently were unable to control infection with an avirulent strain (H37Ra). Importantly, healthy human AM infected with H37Ra equally demonstrated diminished energetics, recapitulating our observation in the murine model system. However, the results from seahorse showed that the shift towards glycolysis in both AM and BMDM was inhibited by H37Rv. We further demonstrated that pharmacological (e.g. metformin or the iron chelator desferrioxamine) reprogramming of AM towards glycolysis reduced necrosis and enhanced AM capacity to control H37Rv growth. Together, our results indicate that the unique bioenergetics of AM renders these cells a perfect target for Mtb survival and that metabolic reprogramming may be a viable host targeted therapy against TB.
    Keywords:  cell death programs; immunity; immunometabolism; metabolic reprograming; pulmonary macrophages; tuberculosis
  16. Allergy. 2023 Feb 13.
      BACKGROUND: Early-life microbial colonization of the skin may modulate the immune system and impact the development of atopic dermatitis (AD) and allergic diseases later in life. To address this question, we assessed the association between the skin microbiome and AD, skin barrier integrity and allergic diseases in the first year of life. We further explored the evolution of the skin microbiome with age and its possible determinants, including delivery mode.METHODS: Skin microbiome was sampled from the lateral upper arm on the first day of life, and at 3, 6 and 12 months of age. Bacterial communities were assessed by 16S rRNA gene amplicon sequencing in 346 infants from the PreventADALL population-based birth cohort study, representing 970 samples. Clinical investigations included skin examination and skin barrier function measured as trans-epidermal water loss (TEWL) at the site and time of microbiome sampling at 3, 6 and 12 months. Parental background information was recorded in electronic questionnaires, and delivery mode (including vaginal delivery (VD), VD in water, elective caesarean section (CS) and emergency CS) was obtained from maternal hospital charts.
    RESULTS: Strong temporal variations in skin bacterial community composition were found in the first year of life, with distinct patterns associated with different ages. Confirming our hypothesis, skin bacterial community composition in the first year of life was associated with skin barrier integrity and later onsets of AD. Delivery mode had a strong impact on the microbiome composition at birth, with each mode leading to distinct patterns of colonization. Other possible determinants of the skin microbiome were identified, including environmental and parental factors as well as breastfeeding.
    CONCLUSION: Skin microbiome composition during infancy is defined by age, transiently influenced by delivery mode as well as environmental, parental factors, breastfeeding, and associated with skin barrier integrity and the onset of AD.
    Keywords:  atopic dermatitis; cohort study; infancy; microbiome; skin
  17. Cell Biochem Funct. 2023 Feb 16.
      Creating cellular homeostasis within a defined tissue typically relates to the processes of apoptosis and efferocytosis. A great example here is cell debris that must be removed to prevent unwanted inflammatory responses and then reduce autoimmunity. In view of that, defective efferocytosis is often assumed to be responsible for the improper clearance of apoptotic cells (ACs). This predicament triggers off inflammation and even results in disease development. Any disruption of phagocytic receptors, molecules as bridging groups, or signaling routes can also inhibit macrophage efferocytosis and lead to the impaired clearance of the apoptotic body. In this line, macrophages as professional phagocytic cells take the lead in the efferocytosis process. As well, insufficiency in macrophage efferocytosis facilitates the spread of a wide variety of diseases, including neurodegenerative diseases, kidney problems, types of cancer, asthma, and the like. Establishing the functions of macrophages in this respect can be thus useful in the treatment of many diseases. Against this background, this review aimed to recapitulate the knowledge about the mechanisms related to macrophage polarization under physiological or pathological conditions, and shed light on its interaction with efferocytosis.
    Keywords:  M1/M2 polarization; apoptotic cell clearance; efferocytosis; inflammation; macrophage polarization
  18. Infect Dis Immun. 2022 Oct;2(4): 248-252
      Innate immune responses are the host's first line of defense against human immunodeficiency virus type 1 (HIV-1) infection, with pattern recognition receptors detecting viral specific pathogen-associated molecular patterns and initiating antiviral responses. In response to HIV-1 nucleic acids or proteins, some pattern recognition receptors have the ability to assemble a large multiprotein complex called the inflammasome, which triggers pro-inflammatory cytokine release and a form of lytic programmed cell death called pyroptosis. Here, we review our current understanding of the mechanism of the inflammasome in sensing HIV-1 infection. Furthermore, we discuss the contribution of inflammasome activation in HIV-1 pathogenesis as well as potential strategies of targeting inflammasome activation for the treatment of HIV-1 infection.
    Keywords:  CARD8 protein; HIV-1; Inflammasomes; Pyroptosis
  19. J Endocrinol. 2023 Feb 01. pii: JOE-22-0184. [Epub ahead of print]
      The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is an oligomeric complex that assembles in response to exogenous signals of pathogen infection and endogenous danger signals of non-microbial origin. When NLRP3 inflammasome assembly activates caspase-1, it promotes the maturation and release of the inflammatory cytokines interleukin-1B and IL-18. Aberrant activation of the NLRP3 inflammasome has been implicated in various diseases, including chronic inflammatory, metabolic, and cardiovascular diseases. The NLRP3 inflammasome can be activated through several principal mechanisms, including K+ efflux, lysosomal damage, and the production of mitochondrial reactive oxygen species. Interestingly, metabolic danger signals activate the NLRP3 inflammasome to induce metabolic diseases. NLRP3 contains three crucial domains: an N-terminal pyrin domain, a central nucleotide-binding domain, and a C-terminal leucine-rich-repeat domain. Protein-protein interactions act as a "pedal or brake" to control the activation of the NLRP3 inflammasome. In this review, we present the mechanisms underlying NLRP3 inflammasome activation after induction by metabolic danger signals or via the protein-protein interactions with NLRP3 that likely occur in metabolic diseases. Understanding these mechanisms will enable the development of specific inhibitors to treat NLRP3-related metabolic diseases.
  20. Front Allergy. 2023 ;4 1093800
      The "epithelial barrier hypothesis" states that a barrier dysfunction can result in allergy development due to tolerance breakdown. This barrier alteration may come from the direct contact of epithelial and immune cells with the allergens, and indirectly, through deleterious effects caused by environmental changes triggered by industrialization, pollution, and changes in the lifestyle. Apart from their protective role, epithelial cells can respond to external factors secreting IL-25 IL-33, and TSLP, provoking the activation of ILC2 cells and a Th2-biased response. Several environmental agents that influence epithelial barrier function, such as allergenic proteases, food additives or certain xenobiotics are reviewed in this paper. In addition, dietary factors that influence the allergenic response in a positive or negative way will be also described here. Finally, we discuss how the gut microbiota, its composition, and microbe-derived metabolites, such as short-chain fatty acids, alter not only the gut but also the integrity of distant epithelial barriers, focusing this review on the gut-lung axis.
    Keywords:  SCFAs; allergy; asthma; epithelial barrier; exposome; food allergy; gut-lung axis; microbiota
  21. Theranostics. 2023 ;13(3): 991-1009
      Background: Complete abolition of alveolar epithelial cells (AECs) is characteristic of end-stage lung disease. Transplantation therapy of type II AECs (AEC-IIs) or AEC-IIs-derived exosomes (ADEs) have been proposed as a means of repairing injury and preventing fibrosis. However, the mechanism by which ADEs balances airway immunity and alleviates damage and fibrosis remains unknown. Methods: We investigated STIM-activating enhancer-positive ADEs (STIMATE+ ADEs) in the lung of 112 ALI/ARDS and 44 IPF patients, and observed the correlation between STIMATE+ ADEs and subpopulation proportion and metabolic status of tissue-resident alveolar macrophages (TRAMs). We constructed the conditional knockout mice STIMATE sftpc , in which STIMATE was specifically knocked out in mouse AEC-IIs and observed the effects of STIMATE+ ADEs deficiency on disease progression, immune selection and metabolic switching of TRAMs. We constructed a BLM-induced AEC-IIs injury model to observe the salvage treatment of damage/fibrosis progression with STIMATE+ ADEs supplementation. Results: In clinical analysis, the distinct metabolic phenotypes of AMs in ALI/ARFS and IPF were significantly perturbed by STIMATE+ ADEs. The immune and metabolic status of TRAMs in the lungs of STIMATE sftpc mice was imbalanced, resulting in spontaneous inflammatory injury and respiratory disorders. STIMATE+ ADEs are taken up by tissue-resident alveolar macrophages TRAMs to regulate high Ca2+ responsiveness and long-term Ca2+ signal transduction, which maintains M2-like immunophenotype and metabolism selection. This involves calcineurin (CaN)-PGC-1α pathway mediated mitochondrial biogenesis and mtDNA coding. In a bleomycin-induced mouse fibrosis model, supplementation with inhaled STIMATE+ ADEs lessened early acute injury, prevented advanced fibrosis, alleviated ventilatory impairment and reduced mortality.
    Keywords:  ALI/ARDS; Alveolar macrophages; Exosome; STIMATE; Type 2 alveolar epithelial.
  22. Nat Metab. 2023 Feb 16.
      Resolving-type macrophages prevent chronic inflammation by clearing apoptotic cells through efferocytosis. These macrophages are thought to rely mainly on oxidative phosphorylation, but emerging evidence suggests a possible link between efferocytosis and glycolysis. To gain further insight into this issue, we investigated molecular-cellular mechanisms involved in efferocytosis-induced macrophage glycolysis and its consequences. We found that efferocytosis promotes a transient increase in macrophage glycolysis that is dependent on rapid activation of the enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2), which distinguishes this process from glycolysis in pro-inflammatory macrophages. Mice transplanted with activation-defective PFKFB2 bone marrow and then subjected to dexamethasone-induced thymocyte apoptosis exhibit impaired thymic efferocytosis, increased thymic necrosis, and lower expression of the efferocytosis receptors MerTK and LRP1 on thymic macrophages compared with wild-type control mice. In vitro mechanistic studies revealed that glycolysis stimulated by the uptake of a first apoptotic cell promotes continual efferocytosis through lactate-mediated upregulation of MerTK and LRP1. Thus, efferocytosis-induced macrophage glycolysis represents a unique metabolic process that sustains continual efferocytosis in a lactate-dependent manner. The differentiation of this process from inflammatory macrophage glycolysis raises the possibility that it could be therapeutically enhanced to promote efferocytosis and resolution in chronic inflammatory diseases.
  23. Front Immunol. 2023 ;14 1105309
      Interferons (IFNs), IFN-stimulated genes (ISGs), and inflammatory cytokines mediate innate immune responses, and are essential to establish an antiviral response. Within the innate immune responses, retinoic acid-inducible gene I (RIG-I) is a key sensor of virus infections, mediating the transcriptional induction of IFNs and inflammatory proteins. Nevertheless, since excessive responses could be detrimental to the host, these responses need to be tightly regulated. In this work, we describe, for the first time, how knocking-down or knocking-out the expression of IFN alpha-inducible protein 6 (IFI6) increases IFN, ISG, and pro-inflammatory cytokine expression after the infections with Influenza A Virus (IAV), Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), and Sendai Virus (SeV), or poly(I:C) transfection. We also show how overexpression of IFI6 produces the opposite effect, in vitro and in vivo, indicating that IFI6 negatively modulates the induction of innate immune responses. Knocking-out or knocking-down the expression of IFI6 diminishes the production of infectious IAV and SARS-CoV-2, most likely because of its effect on antiviral responses. Importantly, we report a novel interaction of IFI6 with RIG-I, most likely mediated through binding to RNA, that affects RIG-I activation, providing a molecular mechanism for the effect of IFI6 on negatively regulating innate immunity. Remarkably, these new functions of IFI6 could be targeted to treat diseases associated with an exacerbated induction of innate immune responses and to combat viral infections, such as IAV and SARS-CoV-2.
    Keywords:  IFI6; RIG-I; RNA binding; coronavirus; inflammation; influenza virus; innate immunity; interferon
  24. Microb Pathog. 2023 Feb 10. pii: S0882-4010(23)00059-1. [Epub ahead of print]177 106026
      Klebsiella pneumoniae (K. pneumoniae) is a common cause of nosocomial infection, which causing disseminated infections such as cystitis, pneumonia and sepsis. K. pneumoniae is intrinsic resistant to penicillin, and members of the population usually have acquired resistance to a variety of antibiotics, which makes it a major threat to clinical and public health. Bacteria can colonize on or within the hosts, accompanied by growth and reproduction of the organisms, but no clinical symptoms are presented. As the "first step" of bacterial infection, colonization in the hosts is of great importance. Colonization of bacteria can last from days to years, with resolution influenced by immune response to the organism, competition at the site from other organisms and, sometimes, use of antimicrobials. Colonized pathogenic bacteria cause healthcare-associated infections at times of reduced host immunity, which is an important cause of clinical occurrence of postoperative complications and increased mortality in ICU patients. Though, K. pneumoniae is one of the most common conditional pathogens of hospital-acquired infections, the mechanisms of K. pneumoniae colonization in humans are not completely clear. In this review, we made a brief summary of the molecular basis of K. pneumoniae colonization in the upper respiratory tract and intestinal niche, and provided new insights for understanding the pathogenesis of K. pneumoniae.
    Keywords:  Colonization; Host; Infection; Klebsiella pneumoniae; Molecular basis; Pathogensis