bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2024–10–06
38 papers selected by
Chun-Chi Chang, Universitäts Spital Zürich
  1. Trained immunity of synovial macrophages is associated with exacerbated joint inflammation and damage after Staphylococcus aureus infection.
  2. Immunoresponsive Gene 1 Facilitates TLR4-agonist-Induced Augmentation of Innate Antimicrobial Immunity.
  3. Siglecs as modulators of macrophage phenotype and function.
  4. Advances on physiology and pathology of subpopulations of macrophages in the lung tissue.
  5. Phenotypic Variation in Staphylococcus aureus during Colonisation Involves Antibiotic-Tolerant Cell Types.
  6. Antiviral innate immune memory in alveolar macrophages following SARS-CoV-2 infection ameliorates secondary influenza A virus disease.
  7. The RNA receptor RIG-I binding synthetic oligodeoxynucleotide promotes pneumonia survival.
  8. Intertwining clonality and resistance: Staphylococcus aureus in the antibiotic era.
  9. Biological evaluation of curdlan sulfate-based nanoparticles in trained immunity enhancement: In vitro and in vivo approaches.
  10. Selenoprotein o as a regulator of macrophage metabolism in selenium deficiency-induced lung inflammation.
  11. Molecular mechanisms of emerging inflammasome complexes and their activation and signaling in inflammation and pyroptosis.
  12. Inflammasomes and their role in PANoptosomes.
  13. Oxysterol binding protein regulates the resolution of TLR-induced cytokine production in macrophages.
  14. A Consensus on Staphylococcus aureus Exacerbated Atopic Dermatitis and the Need for a Novel Treatment.
  15. Carbohydrate metabolism in supporting and regulating neutrophil effector functions.
  16. The human gut microbiome in health and disease: time for a new chapter?
  17. Streptococcus mutans outer membrane vesicles affect inflammasome activation and the glycolysis of macrophages.
  18. Peroxisomal homeostasis in metabolic diseases and its implication in ferroptosis.
  19. RAMP1 Signaling Mitigates Acute Lung Injury by Distinctively Regulating Alveolar and Monocyte-Derived Macrophages.
  20. TCA metabolism regulates DNA hypermethylation in LPS and Mycobacterium tuberculosis-induced immune tolerance.
  21. Dysbiosis and diabetic foot ulcers: A metabolic perspective of Staphylococcus aureus infection.
  22. Impact of Oil-in-Water Adjuvanted β-Glucan on Innate Immune Memory in Piglets.
  23. Fatty acid metabolism in neutrophils promotes lung damage and bacterial replication during tuberculosis.
  24. Multi-Level Proteomics Reveals Epigenetic Signatures in BCG-mediated Macrophage Activation.
  25. WISP1 and Macrophage Migration Inhibitory Factor in Respiratory Inflammation: Novel Insights and Therapeutic Potentials for Asthma and COPD.
  26. Mechanisms and Implications of Phenotypic Switching in Bacterial Pathogens.
  27. Monocyte-derived macrophages are too much of a good thing in lung fibrosis.
  28. Salivary polyreactive antibodies, airway bacteria, and recurrent respiratory infection severity.
  29. Changes in Innate Immunity and Microbiome in Different Aging Phenotypes.
  30. The role of microbial indole metabolites in tumor.
  31. Metabolic interactions shape emergent biofilm structures in a conceptual model of gut mucosal bacterial communities.
  32. Phosphorylation of caspases by a bacterial kinase inhibits host programmed cell death.
  33. In vitro 3D skin culture and its sustainability in toxicology: a narrative review.
  34. Overview of ferroptosis and pyroptosis in acute liver failure.
  35. Repair and regeneration: ferroptosis in the process of remodeling and fibrosis in impaired organs.
  36. Clarithromycin Modulates Neutrophilic Inflammation Induced by Prevotella intermedia in Human Airway Epithelial Cells.
  37. RACK1 and NEK7 mediate GSDMD-dependent macrophage pyroptosis upon Streptococcus suis infection.
  38. Immunometabolic Chaos in Septic Shock.
  1. Inflamm Res. 2024 Sep 28.
    Trained immunity of synovial macrophages is associated with exacerbated joint inflammation and damage after Staphylococcus aureus infection.
    Peter Silva Rocha, Adryan Aparecido Silva, Celso Martins Queiroz-Junior, Amanda Dias Braga, Thaiane Pinto Moreira, Mauro Martins Teixeira, Flávio Almeida Amaral.
       OBJECTIVES: Investigate whether and which synoviocytes would acquire trained immunity characteristics that could exacerbate joint inflammation following a secondary Staphylococcus aureus infection.
    METHODS: Lipopolysaccharide (LPS) and S. aureus were separately or double injected (21 days of interval) into the tibiofemoral joint cavity of male C57BL/6 mice. At different time points after these stimulations, mechanical nociception was analyzed followed by the analysis of signs of inflammation and damage in the affected joints. The trained immunity markers, including the glycolytic and mTOR pathway, were analyzed in whole tissue or isolated synoviocytes. A group of mice was treated with Rapamycin, an mTOR inhibitor before LPS or S. aureus stimulation.
    RESULTS: The double LPS - S. aureus hit promoted intense joint inflammation and damage compared to single joint stimulation, including markers in synoviocyte activation, production of proinflammatory cytokines, persistent nociception, and bone damage, despite not reducing the bacterial clearance. The double LPS - S. aureus hit joints increased the synovial macrophage population expressing CX3CR1 alongside triggering established epigenetic modifications associated with trained immunity events in these cells, such as the upregulation of the mTOR signaling pathway (p-mTOR and HIF1α) and the trimethylation of histone H3. Mice treated with Rapamycin presented reduced CX3CR1+ macrophage activation, joint inflammation, and bone damage.
    CONCLUSIONS: There is a trained immunity phenotype in CX3CR1+ synovial macrophages that contributes to the exacerbation of joint inflammation and damage during septic arthritis caused by S. aureus.
    Keywords:   Staphylococcus aureus ; Arthritis; Inflammation; Septic arthritis; Synoviocytes; Trained Immunity
    DOI:  https://doi.org/10.1007/s00011-024-01946-w
  2. J Leukoc Biol. 2024 Oct 01. pii: qiae198. [Epub ahead of print]
    Immunoresponsive Gene 1 Facilitates TLR4-agonist-Induced Augmentation of Innate Antimicrobial Immunity.
    Margaret A McBride, Katherine R Caja, Tazeen K Patil, Allison M Owen, Liming Luan, Julia K Bohannon, Antonio Hernandez, Cody L Stothers, Irina A Trenary, Mohsin Rahim, Jamey D Young, M Wade Calcutt, Victoria R Stephens, Xenia Davis, Mary A Oliver, Dan Hao, Clara Si, Malik McRae, Kenny K Nguyen, Nicholas S Davis, Jingbin Wang, Naeem K Patil, Edward R Sherwood.
      Treatment with the toll-like receptor (TLR) 4 agonist monophosphoryl lipid A (MPLA) conditions innate immunocytes to respond robustly to subsequent infection, a phenotype termed innate immune memory. Our published studies show that metabolic reprogramming of macrophages is a prominent feature of the memory phenotype. We undertook studies to define the functional contributions of tricarboxylic acid (TCA) cycle reprogramming to innate immune memory. We observed that priming of wild type (WT) mice with MPLA potently facilitated accumulation of the TCA cycle metabolite itaconate at sites of infection and enhanced microbial clearance. Augmentation of itaconate accumulation and microbial clearance was ablated in immuneresponsive gene 1 (Irg1) -deficient mice. We further observed that MPLA potently induces expression of Irg1 and accumulation of itaconate in macrophages. Compared to WT macrophages, the ability of Irg1-deficient macrophages to kill Pseudomonas aeruginosa was impaired. We further observed that itaconate is directly antimicrobial against P. aeruginosa at pH 5, which is characteristic of the phagolysosome, and is facilitated by reactive oxygen species. MPLA-induced augmentation of glycolysis, oxidative phosphorylation and accumulation of the TCA cycle metabolites succinate and malate was decreased in Irg1 KO macrophages compared to WT controls. RNA sequencing revealed suppressed transcription of genes associated with phagolysosome function and increased expression of genes associated with cytokine production and chemotaxis in Irg1 deficient macrophages. This study identifies a contribution of itaconate to MPLA-induced augmentation of innate antimicrobial immunity via facilitation of microbial killing as well as impact on metabolic and transcriptional adaptations.
    Keywords:  Immune Responsive Gene; Innate Immune Memory; Itaconate; Macrophages; Monophosphoryl Lipid A
    DOI:  https://doi.org/10.1093/jleuko/qiae198
  3. Semin Immunol. 2024 Oct 01. pii: S1044-5323(24)00025-3. [Epub ahead of print]73 101887
    Siglecs as modulators of macrophage phenotype and function.
    Emily N Kukan, Gabrielle L Fabiano, Brian A Cobb.
      The sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of receptors expressed widely on cells of the hematopoietic system. Siglecs recognize terminal sialic acid residues on glycans and often initiate intracellular signaling upon ligation. Cells can express several Siglec family members concurrently with each showing differential specificities for sialic acid linkages to the underlying glycan as well as varied hydroxyl substitutions, allowing these receptors to fine tune downstream responses. Macrophages are among the many immune cells that express Siglec family members. Macrophages exhibit wide diversity in their phenotypes and functions, and this diversity is often mediated by signals from the local environment, including those from glycans. In this review, we detail the known expression of Siglecs in macrophages while focusing on their functional importance and potential clinical relevance.
    Keywords:  Immune checkpoint; Macrophage; Sialic acid; Siglec
    DOI:  https://doi.org/10.1016/j.smim.2024.101887
  4. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2024 Sep 29. 1-9
    Advances on physiology and pathology of subpopulations of macrophages in the lung tissue.
    Xiaohui Zhong, Chengjie Lyu, Dengming Lai, Qiang Shu.
      The macrophages are vital in maintaining tissue homeostasis in the lungs by modulating and regulating immune responses. Based on different origins and anatomical locations, macrophages in the lungs are categorized into alveolar macrophages, interstitial macrophages, perivascular macrophages, and inflammatory macrophages. Alveolar macro-phages are located in the alveolar spaces and are primarily responsible for maintaining alveolar surfactant homeostasis, defending against pathogens and regulating immune responses. Interstitial macrophages function to maintain homeostasis, regulate immunity and anti-inflammation within the lung tissue. Perivascular macrophages play a crucial role in inhibiting lung inflammation, improving pulmonary fibrosis, and regulating lung tumor progression due to antigen-presenting and immunomodulatory effects. Inflammatory macrophages, which are differentiated from monocytes during inflammation, regulate the inflammatory process. This article reviews the origins of various subpopulations of macro-phages in the lung tissue and their physiological and pathological functions, discusses the underlying mechanisms and potential therapeutic targets.
    Keywords:  Immune; Inflammation; Lung tissue; Macrophage; Pathological; Physiological; Review
    DOI:  https://doi.org/10.3724/zdxbyxb-2024-0129
  5. Antibiotics (Basel). 2024 Sep 05. pii: 845. [Epub ahead of print]13(9):
    Phenotypic Variation in Staphylococcus aureus during Colonisation Involves Antibiotic-Tolerant Cell Types.
    Chloe M Burford-Gorst, Stephen P Kidd.
      Staphylococcus aureus is a bacterial species that is commonly found colonising healthy individuals but that presents a paradoxical nature: simultaneously, it can migrate within the body and cause a range of diseases. Many of these become chronic by resisting immune responses, antimicrobial treatment, and medical intervention. In part, this ability to persist can be attributed to the adoption of multiple cell types within a single cellular population. These dynamics in the S. aureus cell population could be the result of its interplay with host cells or other co-colonising bacteria-often coagulase-negative Staphylococcal (CoNS) species. Further understanding of the unique traits of S. aureus alternative cell types, the drivers for their selection or formation during disease, as well as their presence even during non-pathological colonisation could advance the development of diagnostic tools and drugs tailored to target specific cells that are eventually responsible for chronic infections.
    Keywords:  Staphylococcus aureus; antibiotic tolerance; coagulase-negative Staphylococcal species; small colony variants
    DOI:  https://doi.org/10.3390/antibiotics13090845
  6. Immunity. 2024 Sep 27. pii: S1074-7613(24)00417-5. [Epub ahead of print]
    Antiviral innate immune memory in alveolar macrophages following SARS-CoV-2 infection ameliorates secondary influenza A virus disease.
    Alexander Lercher, Jin-Gyu Cheong, Michael J Bale, Chenyang Jiang, Hans-Heinrich Hoffmann, Alison W Ashbrook, Tyler Lewy, Yue S Yin, Corrine Quirk, Emma J DeGrace, Luis Chiriboga, Brad R Rosenberg, Steven Z Josefowicz, Charles M Rice.
      Pathogen encounter can result in epigenetic remodeling that shapes disease caused by heterologous pathogens. Here, we examined innate immune memory in the context of commonly circulating respiratory viruses. Single-cell analyses of airway-resident immune cells in a disease-relevant murine model of SARS-CoV-2 recovery revealed epigenetic reprogramming in alveolar macrophages following infection. Post-COVID-19 human monocytes exhibited similar epigenetic signatures. In airway-resident macrophages, past SARS-CoV-2 infection increased activity of type I interferon (IFN-I)-related transcription factors and epigenetic poising of antiviral genes. Viral pattern recognition and canonical IFN-I signaling were required for the establishment of this innate immune memory and augmented secondary antiviral responses. Antiviral innate immune memory mounted by airway-resident macrophages post-SARS-CoV-2 was necessary and sufficient to ameliorate secondary disease caused by influenza A virus and curtailed hyperinflammatory dysregulation and mortality. Our findings provide insights into antiviral innate immune memory in the airway that may facilitate the development of broadly effective therapeutic strategies.
    Keywords:  SARS-CoV-2; alveolar macrophages; epigenetic memory; immunology; influenza; innate immune memory; lung disease; respiratory virus; trained immunity; viral infection
    DOI:  https://doi.org/10.1016/j.immuni.2024.08.018
  7. JCI Insight. 2024 Oct 01. pii: e180584. [Epub ahead of print]
    The RNA receptor RIG-I binding synthetic oligodeoxynucleotide promotes pneumonia survival.
    Yongxing Wang, Vikram V Kulkarni, Jezreel Pantaleón García, Michael K Longmire, Mathilde Lethier, Stephen Cusack, Scott E Evans.
      Pneumonia is a worldwide threat to public health, demanding novel preventative and therapeutic strategies. The lung epithelium is a critical environmental interface that functions as a physical barrier to pathogen invasion while also actively sensing and responding to pathogens. We have reported that stimulating lung epithelial cells with a combination therapeutic consisting of a diacylated lipopeptide and a synthetic CpG oligodeoxynucleotide (ODN) induces synergistic pneumonia protection against a wide range of pathogens. We report here that mice deficient in Toll-like receptor 9 (TLR9), the previously described receptor for ODN, still displayed partial ODN-induced protection. This prompted us to seek an alternate ODN receptor, and we discovered by mass spectroscopy that the RNA sensor RIG-I could also bind DNA-like ODN. ODN binding by RIG-I resulted in MAVS-dependent pneumonia-protective signaling events. While RIG-I is essential to native defenses against viral infections, we report that therapeutic RIG-I activation with ODN promoted pathogen killing and host survival following both viral and bacterial challenges. These data indicate that maximal ODN-induced pneumonia protection requires activation of both TLR9/MyD88 and RIG-I/MAVS signaling pathways. These findings not only identify what we believe to be a novel pattern recognition receptor for DNA-like molecules, but reveal a potential therapeutic strategy to protect susceptible individuals against lethal pneumonias during periods of peak vulnerability.
    Keywords:  Bacterial infections; Cell biology; Immunology; Influenza; Innate immunity
    DOI:  https://doi.org/10.1172/jci.insight.180584
  8. J Clin Invest. 2024 Oct 01. pii: e185824. [Epub ahead of print]134(19):
    Intertwining clonality and resistance: Staphylococcus aureus in the antibiotic era.
    Henry F Chambers, Vance G Fowler.
      
    DOI:  https://doi.org/10.1172/JCI185824
  9. Int J Biol Macromol. 2024 Oct 01. pii: S0141-8130(24)07017-X. [Epub ahead of print] 136208
    Biological evaluation of curdlan sulfate-based nanoparticles in trained immunity enhancement: In vitro and in vivo approaches.
    Yipan Chen, Zuyi Li, Honglei Jiang, Longkun Wang, Yuhe Zhang, Xinke Zhang, Wenjie Jiang, Fengshan Wang.
       OBJECTIVES: Recently, more and more evidences suggest that β-glucans can induce trained immunity and non-specific protections against pathogens. However, most of the reports evaluated the immunological activities of β-glucans through injection route but no nasal inhalation. In this study, the effects of curdlan sulfate-based nanoparticles, CS/O-HTCC on trained immunity through intranasal administration were evaluated.
    METHODS: Macrophages were treated with CS/O-HTCC and the metabolisms of the macrophages were detected. Mice were intranasal administered with CS/O-HTCC for 3 times with a 14 days interval, then the antitumor or infection prevention effects were assessed.
    RESULTS: In vitro, CS/O-HTCC enhanced the macrophage metabolism significantly through upregulating glycolysis (26.1 ± 4.3 mpH/min) and oxidative phosphorylation (36.0 ± 9.0 pmol/min) compared with that of negative group (7.5 ± 2.3 mpH/min and 19.5 ± 4.9 pmol/min). In vivo, CS/O-HTCC inhibited lung metastasis of B16F10 tumor cells and improved the survival time (26.5 days) of the nmice compared with negative group (19.5 days). Moreover, CS/O-HTCC prevented the lung infections by Escherichia coli or Streptococcus pneumoniae (less bacterial residual) and reduced lung damages.
    CONCLUSIONS: CS/O-HTCC can induce trained immunity through enhancing the metabolism of macrophages and enhance the non-specific protection against pathogens through intranasal immunization.
    Keywords:  Curdlan sulfate; Mucosal adjuvant; Trained immunity
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.136208
  10. Int J Biol Macromol. 2024 Oct 01. pii: S0141-8130(24)07041-7. [Epub ahead of print] 136232
    Selenoprotein o as a regulator of macrophage metabolism in selenium deficiency-induced lung inflammation.
    Yongzhen Du, Yu Xia, Tong Xu, Haojie Hu, Yujiao He, Muyue Zhang, Shu Li.
      Selenium (Se) deficiency induces an inflammatory response in the lungs, but the underlying mechanisms are unknown. Selenoprotein O (SelO) is the largest selenoprotein in terms of molecular weight, yet its potential biological functions have yet to be characterized. Our study revealed that Se deficiency leads to an imbalance in the expression of pro-inflammatory "M1" macrophages and anti-inflammatory "M2" macrophages in alveolar macrophages (AMs) and interstitial macrophages (IMs) and contributed to the development of lung inflammation. Through the analysis of differentially expressed selenoproteins, we identified SelO as a potential regulator of the imbalance in pulmonary macrophage polarization caused by Se deficiency. In vitro experiments showed that SelO knockdown enhanced the polarization of M1 macrophages while suppressing that of M2 macrophages. In addition, SelO knockdown reprogrammed macrophage metabolism to glycolysis, disrupting oxidative phosphorylation (OXPHOS). Mechanistically, SelO primarily targets mitochondrial transcription factor A (TFAM), which plays a crucial role in the transcription and replication of mitochondrial DNA (mtDNA) and is essential for mitochondrial biogenesis and energy metabolism. The deficiency of SelO affects TFAM, resulting in its uncontrolled degradation, which compromises mitochondrial function and energy metabolism. In summary, the findings presented here offer significant theoretical insights into the physiological functions of SelO.
    Keywords:  Macrophage polarization; Metabolic reprogramming; Pulmonary inflammation; Se deficiency; Selenoprotein O; TFAM
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.136232
  11. Immunol Rev. 2024 Oct 01.
    Molecular mechanisms of emerging inflammasome complexes and their activation and signaling in inflammation and pyroptosis.
    Abhimanu Pandey, Zheyi Li, Manjul Gautam, Aritra Ghosh, Si Ming Man.
      Inflammasomes are multi-protein complexes that assemble within the cytoplasm of mammalian cells in response to pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), driving the secretion of the pro-inflammatory cytokines IL-1β and IL-18, and pyroptosis. The best-characterized inflammasome complexes are the NLRP3, NAIP-NLRC4, NLRP1, AIM2, and Pyrin canonical caspase-1-containing inflammasomes, and the caspase-11 non-canonical inflammasome. Newer inflammasome sensor proteins have been identified, including NLRP6, NLRP7, NLRP9, NLRP10, NLRP11, NLRP12, CARD8, and MxA. These inflammasome sensors can sense PAMPs from bacteria, viruses and protozoa, or DAMPs in the form of mitochondrial damage, ROS, stress and heme. The mechanisms of action, physiological relevance, consequences in human diseases, and avenues for therapeutic intervention for these novel inflammasomes are beginning to be realized. Here, we discuss these emerging inflammasome complexes and their putative activation mechanisms, molecular and signaling pathways, and physiological roles in health and disease.
    Keywords:  PANoptosis; PANoptosome; autoimmunity; autoinflammation; bacteria; cancer; caspase‐1; caspase‐11; caspase‐4; caspase‐5; cell death; cytokines; gasdermin D; immunity; infection; inflammatory caspases; interferons; lipopolysaccharide; parasites; pattern‐recognition receptors; viruses
    DOI:  https://doi.org/10.1111/imr.13406
  12. Curr Opin Immunol. 2024 Sep 27. pii: S0952-7915(24)00079-7. [Epub ahead of print]91 102489
    Inflammasomes and their role in PANoptosomes.
    Vinod Nadella, Thirumala-Devi Kanneganti.
      Inflammasomes are multiprotein signaling structures in the innate immune system that drive cell death and inflammatory responses. These protein complexes generally comprise an innate immune sensor, the adaptor protein ASC, and the inflammatory protease caspase-1. Inflammasomes are formed when a cytosolic sensor, also known as a pattern recognition receptor, senses its cognate ligand, which can include microbial components, endogenous damage/danger signals, or environmental stimuli. Inflammasome assembly leads to autoproteolytic cleavage and activation of caspase-1. This activation, in turn, induces proteolytic maturation and release of the proinflammatory cytokines interleukin (IL)-1β and IL-18, and the activation of the pore-forming molecule gasdermin D to induce cell death, known as pyroptosis. Recent studies have identified inflammasomes as integral components of larger cell death complexes, known as PANoptosomes. These PANoptosomes regulate PANoptosis, an innate immune cell death pathway initiated by innate immune sensors and driven by caspases and receptor-interacting serine/threonine protein kinases. PANoptosome assembly and activation leads to cell lysis, inflammation, and the release of proinflammatory cytokines, damage-associated molecular patterns, and alarmins. In this review, we discuss the current understanding of different inflammasomes and their role in PANoptosomes.
    DOI:  https://doi.org/10.1016/j.coi.2024.102489
  13. Proc Natl Acad Sci U S A. 2024 Aug 13. 121(33): e2406492121
    Oxysterol binding protein regulates the resolution of TLR-induced cytokine production in macrophages.
    Alan H Diercks, Irina S Podolskaia, Tara A Murray, Ana N Jahn, Dat Mai, Dong Liu, Lynn M Amon, Yoshimi Nakagawa, Hitoshi Shimano, Alan Aderem, Elizabeth S Gold.
      Toll-like receptors (TLRs) on macrophages sense microbial components and trigger the production of numerous cytokines and chemokines that mediate the inflammatory response to infection. Although many of the components required for the activation of the TLR pathway have been identified, the mechanisms that appropriately regulate the magnitude and duration of the response and ultimately restore homeostasis are less well understood. Furthermore, a growing body of work indicates that TLR signaling reciprocally interacts with other fundamental cellular processes, including lipid metabolism but only a few specific molecular links between immune signaling and the macrophage lipidome have been studied in detail. Oxysterol-binding protein (Osbp) is the founding member of a family of lipid-binding proteins with diverse functions in lipid sensing, lipid transport, and cell signaling but its role in TLR responses is not well defined. Here, we demonstrate that altering the state of Osbp with its natural ligand, 25-hydroxycholesterol (25HC), or pharmacologically, sustains and thereby amplifies Tlr4-induced cytokine production in vitro and in vivo. CRISPR-induced knockdown of Osbp abrogates the ability of these ligands to sustain TLR responses. Lipidomic analysis suggested that the effect of Osbp on TLR signaling may be mediated by alterations in triglyceride production and treating cells with a Dgat1 inhibitor, which blocks triglyceride production and completely abrogates the effect of Osbp on TLR signaling. Thus, Osbp is a sterol sensor that transduces perturbations of the lipidome to modulate the resolution of macrophage inflammatory responses.
    Keywords:  25-hydroxycholesterol; Osbp; immunometabolism; macrophage; toll-like receptor
    DOI:  https://doi.org/10.1073/pnas.2406492121
  14. J Drugs Dermatol. 2024 Oct 01. 23(10): 825-832
    A Consensus on Staphylococcus aureus Exacerbated Atopic Dermatitis and the Need for a Novel Treatment.
    Lawrence A Schachner, Anneke Andriessen, Mercedes E Gonzalez, Karan Lal, Adelaide A Hebert, Lawrence F Eichenfield, Peter Lio.
      The skin microbiome is essential for skin barrier function because it inhibits pathogen colonization, and decreased microbiome diversity correlates with increased Staphylococcus aureus (S. aureus) burden and atopic dermatitis (AD) severity. Managing S. aureuss-driven AD in clinical practice remains problematic due to complications such as AD exacerbation, impetigo, abscesses, and invasive infections. This project used a modified Delphi process comprising face-to-face discussions followed by a blinded vote to define 5 final consensus statements. A panel of 6 pediatric dermatologists developed a consensus on S. aureus-driven AD exacerbation, challenges in current treatments for AD with secondary bacterial infections, and new developments to improve patient care and outcomes. The panel's 5 consensus statements provide recommendations for dermatologists, pediatricians, and healthcare providers treating patients with secondary infected AD. These recommendations underscore the importance of recognizing and managing S. aureus skin infection in AD clinical practice and promoting antibiotic stewardship to mitigate resistance. The panel defined a significant unmet need for a single topical AD therapy effective against all symptoms, including pruritus, S. aureus-driven AD exacerbation, infection, and inflammation, across AD severity levels. J Drugs Dermatol. 2024;23(10):825-832. doi:10.36849/JDD.8240.
    DOI:  https://doi.org/10.36849/JDD.2024.8240
  15. Curr Opin Immunol. 2024 Oct 03. pii: S0952-7915(24)00087-6. [Epub ahead of print]91 102497
    Carbohydrate metabolism in supporting and regulating neutrophil effector functions.
    Jorgo Lika, Jing Fan.
      Neutrophils, the first responders of the innate immune system, can turn on a range of effector functions upon activation. Emerging research shows activated neutrophils undergo highly dynamic metabolic rewiring. This metabolic rewiring provides energy and reducing power to fuel effector functions and modulate signaling molecules to regulate neutrophil functions. Here, we review the current understanding of the specific metabolic requirements and regulators of neutrophil migration, neutrophil extracellular traps release, and pathogen killing. Particularly, we discuss how major carbohydrate metabolic pathways, including glycolysis, glycogen cycling, pentose phosphate pathway, and TCA cycle, are rewired upon neutrophil activation to support these functions. Continued investigation into the metabolic regulators of neutrophil functions can lead to therapeutic opportunities in various diseases.
    DOI:  https://doi.org/10.1016/j.coi.2024.102497
  16. Infect Immun. 2024 Sep 30. e0030224
    The human gut microbiome in health and disease: time for a new chapter?
    Jee-Yon Lee, Derek J Bays, Hannah P Savage, Andreas J Bäumler.
      The gut microbiome, composed of the colonic microbiota and their host environment, is important for many aspects of human health. A gut microbiome imbalance (gut dysbiosis) is associated with major causes of human morbidity and mortality. Despite the central part our gut microbiome plays in health and disease, mechanisms that maintain homeostasis and properties that demarcate dysbiosis remain largely undefined. Here we discuss that sorting taxa into meaningful ecological units reveals that the availability of respiratory electron acceptors, such as oxygen, in the host environment has a dominant influence on gut microbiome health. During homeostasis, host functions that limit the diffusion of oxygen into the colonic lumen shelter a microbial community dominated by primary fermenters from atmospheric oxygen. In turn, primary fermenters break down unabsorbed nutrients into fermentation products that support host nutrition. This symbiotic relationship is disrupted when host functions that limit the luminal availability of host-derived electron acceptors become weakened. The resulting changes in the host environment drive alterations in the microbiota composition, which feature an elevated abundance of facultatively anaerobic microbes. Thus, the part of the gut microbiome that becomes imbalanced during dysbiosis is the host environment, whereas changes in the microbiota composition are secondary to this underlying cause. This shift in our understanding of dysbiosis provides a novel starting point for therapeutic strategies to restore microbiome health. Such strategies can either target the microbes through metabolism-based editing or strengthen the host functions that control their environment.
    Keywords:  dysbiosis; ecological guilds; gut microbiome; gut microbiota
    DOI:  https://doi.org/10.1128/iai.00302-24
  17. Microb Pathog. 2024 Oct 02. pii: S0882-4010(24)00461-3. [Epub ahead of print] 106994
    Streptococcus mutans outer membrane vesicles affect inflammasome activation and the glycolysis of macrophages.
    Gongyuan Song, Min Li, Bing Zhou, Hongguang Qi, Jie Guo.
      Recent studies indicate that bacterial outer membrane vesicles (OMVs) play a significant role in bacterial virulence and pathogenicity. Streptococcus mutans (S. mutans), a principal pathogen in dental caries, secretes a substantial number of OMVs. However, the impact of S. mutans OMVs on oral health and their underlying pathogenic mechanisms remain poorly understood. Macrophages were the initial innate immune cells to respond to bacterial invaders and their products. Therefore, we purified S. mutans OMVs, which stimulated macrophages. Compared to controls, RT-PCR and ELISA analyses revealed that S. mutans OMVs significantly increased the production of IL-1β, IL-6, TNF-α and IL-8, with IL-1β being notably elevated. IL-1β production and secretion are tightly regulated by the inflammasome. Western blot analyses demonstrated that S. mutans OMVs upregulated the expression of inflammasome components, including NLRP3, NLRC4, ASC and AIM2, with a marked increase in NLRP3 expression. Silencing different inflammasome components with siRNA revealed a reduction in IL-1β secretion induced by S. mutans OMVs, particularly through NLRP3. Additionally, ATP production and K+ efflux were found to be crucial for NLRP3 activation. Prolonged stimulation with S. mutans OMVs resulted in increased lactate production and elevated expression of glycolysis-related genes Glut-1, PFKFB3, and HK I, indicating that S. mutans OMVs significantly induce macrophage glycolysis. Furthermore, S. mutans OMVs were shown to enhance biofilm formation, increase S. mutans colonisation on epithelial cells, and inhibit macrophage phagocytosis, thereby improving the survival of S. mutans in the oral cavity. In summary, S. mutans OMVs promote the survival of S. mutans in the mouth through multiple mechanisms, potentially influencing the development of dental caries.
    Keywords:  Oral bacteria; S. mutans OMVs; biofilm; glycolysis; inflammasome; macrophages
    DOI:  https://doi.org/10.1016/j.micpath.2024.106994
  18. Cell Commun Signal. 2024 Oct 04. 22(1): 475
    Peroxisomal homeostasis in metabolic diseases and its implication in ferroptosis.
    Jiwei Han, Daheng Zheng, Pu-Ste Liu, Shanshan Wang, Xin Xie.
      Peroxisomes are dynamic organelles involved in various cellular processes, including lipid metabolism, redox homeostasis, and intracellular metabolite transfer. Accumulating evidence suggests that peroxisomal homeostasis plays a crucial role in human health and disease, particularly in metabolic disorders and ferroptosis. The abundance and function of peroxisomes are regulated by a complex interplay between biogenesis and degradation pathways, involving peroxins, membrane proteins, and pexophagy. Peroxisome-dependent lipid metabolism, especially the synthesis of ether-linked phospholipids, has been implicated in modulating cellular susceptibility to ferroptosis, a newly discovered form of iron-dependent cell death. This review discusses the current understanding of peroxisome homeostasis, its roles in redox regulation and lipid metabolism, and its implications in human diseases. We also summarize the main mechanisms of ferroptosis and highlight recent discoveries on how peroxisome-dependent metabolism and signaling influence ferroptosis sensitivity. A better understanding of the interplay between peroxisomal homeostasis and ferroptosis may provide new insights into disease pathogenesis and reveal novel therapeutic strategies for peroxisome-related metabolic disorders and ferroptosis-associated diseases.
    Keywords:  Ferroptosis; Homeostasis; Lipid metabolism; Metabolic disorders; Peroxisome; Redox regulation; Therapeutic strategies
    DOI:  https://doi.org/10.1186/s12964-024-01862-w
  19. Int J Mol Sci. 2024 Sep 20. pii: 10107. [Epub ahead of print]25(18):
    RAMP1 Signaling Mitigates Acute Lung Injury by Distinctively Regulating Alveolar and Monocyte-Derived Macrophages.
    Atsushi Yamashita, Yoshiya Ito, Mayuko Osada, Hiromi Matsuda, Kanako Hosono, Kazutake Tsujikawa, Hirotsugu Okamoto, Hideki Amano.
      Acute respiratory distress syndrome (ARDS) is a life-threatening lung injury that induces cytokine hypersecretion. Receptor activity-modifying protein (RAMP) 1, a subunit of the calcitonin gene-related peptide (CGRP) receptor, regulates the production of cytokines. This study examined the role of RAMP1 signaling during lipopolysaccharide (LPS)-induced acute lung injury (ALI). LPS administration to wild-type (WT) mice depleted alveolar macrophages (AMs) and recruited monocyte-derived macrophages (MDMs) and neutrophils. RAMP1-deficient (RAMP1-/-) mice exhibited higher lung injury scores, cytokine levels, and cytokine-producing neutrophil infiltration. RAMP1-deficient AMs produced more cytokines in response to LPS than WT AMs. Adoptive transfer of RAMP1-deficient AMs to RAMP1-/- mice increased cytokine levels and neutrophil accumulation compared to the transfer of WT AMs. RAMP1-/- mice had reduced MDM recruitment and lower pro-inflammatory and reparative macrophage profiles. Cultured bone marrow (BM)-derived RAMP1-deficient macrophages stimulated with LPS showed decreased expression of pro-inflammatory and pro-repairing genes. CGRP administration to WT mice reduced cytokine production and neutrophil accumulation. These findings indicate that RAMP1 signaling mitigates LPS-induced ALI by inactivating AMs and promoting inflammatory and repair activities of MDMs. Targeting RAMP1 signaling presents a potential therapeutic approach for the treatment of ARDS.
    Keywords:  RAMP1; immunity; macrophage; nerve; neutrophil
    DOI:  https://doi.org/10.3390/ijms251810107
  20. Proc Natl Acad Sci U S A. 2024 Oct 08. 121(41): e2404841121
    TCA metabolism regulates DNA hypermethylation in LPS and Mycobacterium tuberculosis-induced immune tolerance.
    Abhimanyu, Santiago Carrero Longlax, Tomoki Nishiguchi, Malik Ladki, Daanish Sheikh, Amera L Martinez, Emily M Mace, Sandra L Grimm, Thaleia Caldwell, Alexandra Portillo Varela, Rajagopal V Sekhar, Anna M Mandalakas, Mandla Mlotshwa, Sibuse Ginidza, Jeffrey D Cirillo, Robert S Wallis, Mihai G Netea, Reinout van Crevel, Cristian Coarfa, Andrew R DiNardo.
      Severe and chronic infections, including pneumonia, sepsis, and tuberculosis (TB), induce long-lasting epigenetic changes that are associated with an increase in all-cause postinfectious morbidity and mortality. Oncology studies identified metabolic drivers of the epigenetic landscape, with the tricarboxylic acid (TCA) cycle acting as a central hub. It is unknown if the TCA cycle also regulates epigenetics, specifically DNA methylation, after infection-induced immune tolerance. The following studies demonstrate that lipopolysaccharide and Mycobacterium tuberculosis induce changes in DNA methylation that are mediated by the TCA cycle. Infection-induced DNA hypermethylation is mitigated by inhibitors of cellular metabolism (rapamycin, everolimus, metformin) and the TCA cycle (isocitrate dehydrogenase inhibitors). Conversely, exogenous supplementation with TCA metabolites (succinate and itaconate) induces DNA hypermethylation and immune tolerance. Finally, TB patients who received everolimus have less DNA hypermethylation demonstrating proof of concept that metabolic manipulation can mitigate epigenetic scars.
    Keywords:  DNA methylation; Rheostat; immune tolerance; sepsis; tuberculosis
    DOI:  https://doi.org/10.1073/pnas.2404841121
  21. Biomed Pharmacother. 2024 Sep 30. pii: S0753-3322(24)01384-2. [Epub ahead of print]180 117498
    Dysbiosis and diabetic foot ulcers: A metabolic perspective of Staphylococcus aureus infection.
    Ruisi Liu, Jiawei Feng, Yiming Ni, Kaixin Chen, Yuqing Wang, Ting Zhang, Mingmei Zhou, Cheng Zhao.
      Staphylococcus aureus (S. aureus) infection is the most prevalent and resistant bacterial infection, posing a worldwide health risk. Compared with healthy people, diabetes patients with weak immune function and abnormal metabolism are more vulnerable to bacterial infection, which aggravates the intensity of infection and causes a series of common and dangerous complications, such as diabetes foot ulcer (DFU). Due to metabolic abnormalities of diabetic patients, S. aureus on the skin surface of DFU transitions from a commensal to an invasive infection. During this process, S. aureus resists a series of unfavorable conditions for bacterial growth by altering energy utilization and metabolic patterns, and secretes various virulence factors, causing persistent infection. With the emergence of multiple super-resistant bacteria, antibiotic treatment is no longer the only treatment option, and developing new drugs and therapies is urgent. Regulating the metabolic signaling pathway of S. aureus plays a decisive role in regulating its virulence factors and impacts adjuvant therapy for DFU. This article focuses on studying the impact of regulating metabolic signals on the virulence of S. aureus from a metabolism perspective. It provides an outlook on the future direction of the novel development of antimicrobial therapy.
    Keywords:  Diabetic foot ulcer; Immune reaction; Metabolism; Staphylococcus aureus; Virulence factors
    DOI:  https://doi.org/10.1016/j.biopha.2024.117498
  22. Vaccines (Basel). 2024 Aug 29. pii: 982. [Epub ahead of print]12(9):
    Impact of Oil-in-Water Adjuvanted β-Glucan on Innate Immune Memory in Piglets.
    Razieh Ardali, Obdulio Garcia-Nicolas, Catherine Ollagnier, José María Sánchez Carvajal, Maria Levy, Pauline Yvernault, Francisco de Aboim Borges Fialho de Brito, Artur Summerfield.
      The non-specific protective effects offered by the concept of "innate immune memory" might represent a promising strategy to tackle early-life threatening infections. Here we tested the potential of an in vitro selected β-glucan in inducing trained immunity using an in vivo porcine model. We assessed the leukocyte transcriptome using blood transcriptomic module (BTM), proinflammatory cytokines, and clinical scoring after a first "training" and a second "stimulation" phase. The possible induction of innate immune memory was tested during a "stimulation" by an LPS-adjuvanted Mycoplasma hyopneumoniae vaccine (Hyogen®) one day after weaning. Following the "training", no major group differences were found, with the exception of a plasma TNF that was only induced by Adj and Adj_BG treatment. After vaccination, all groups developed similar antibody responses. A significant induction of plasma TNF and IL-1β was found in groups that received Adj and Adj_BG. However, following vaccination, the expected early innate BTMs were only induced by the PBS group. In conclusion, the adjuvant alone, adjuvant-formulated β-glucan, or orally applied β-glucan were unable to enhance innate immune reactivity but rather appeared to promote innate immune tolerance. Such an immune status could have both positive and negative implications during this phase of the piglet's life.
    Keywords:  adjuvant; innate immune memory; innate tolerance; piglets; β-glucan
    DOI:  https://doi.org/10.3390/vaccines12090982
  23. PLoS Pathog. 2024 Oct 04. 20(10): e1012188
    Fatty acid metabolism in neutrophils promotes lung damage and bacterial replication during tuberculosis.
    Poornima Sankar, Ramon Bossardi Ramos, Jamie Corro, Lokesh K Mishra, Tanvir Noor Nafiz, Gunapati Bhargavi, Mohd Saqib, Sibongiseni K L Poswayo, Suraj P Parihar, Yi Cai, Selvakumar Subbian, Anil K Ojha, Bibhuti B Mishra.
      Mycobacterium tuberculosis (Mtb) infection induces a marked influx of neutrophils into the lungs, which intensifies the severity of tuberculosis (TB). The metabolic state of neutrophils significantly influences their functional response during inflammation and interaction with bacterial pathogens. However, the effect of Mtb infection on neutrophil metabolism and its consequent role in TB pathogenesis remain unclear. In this study, we examined the contribution of glycolysis and fatty acid metabolism on neutrophil responses to Mtb HN878 infection using ex-vivo assays and murine infection models. We discover that blocking glycolysis aggravates TB pathology, whereas inhibiting fatty acid oxidation (FAO) yields protective outcomes, including reduced weight loss, immunopathology, and bacterial burden in lung. Intriguingly, FAO inhibition preferentially disrupts the recruitment of a pathogen-permissive immature neutrophil population (Ly6Glo/dim), known to accumulate during TB. Targeting carnitine palmitoyl transferase 1a (Cpt1a)-a crucial enzyme in mitochondrial β-oxidation-either through chemical or genetic methods impairs neutrophils' ability to migrate to infection sites while also enhancing their antimicrobial function. Our findings illuminate the critical influence of neutrophil immunometabolism in TB pathogenesis, suggesting that manipulating fatty acid metabolism presents a novel avenue for host-directed TB therapies by modulating neutrophil functions.
    DOI:  https://doi.org/10.1371/journal.ppat.1012188
  24. Mol Cell Proteomics. 2024 Oct 02. pii: S1535-9476(24)00141-5. [Epub ahead of print] 100851
    Multi-Level Proteomics Reveals Epigenetic Signatures in BCG-mediated Macrophage Activation.
    Zoe Schaefer, John Iradukunda, Evelyn Lumngwena, Kari Basso, Jonathan Blackburn, Ivana Parker.
      The bacillus Calmette-Guérin BCG vaccine (Mycobacterium bovis) is primarily used to prevent tuberculosis (TB) infections but has wide-ranging immunogenic effects. One of its most notable properties is its ability to induce trained immunity, a memory-like response in innate immune cells such as macrophages. Through targeted analyses of well-established histone marks, prior research has shown that these changes are generated through epigenetic modification. Mass spectrometry-based proteomic approaches provide a way to globally profile various aspects of the proteome, providing data to further identify unexplored mechanisms of BCG-mediated immunomodulation. Here we use multi-level proteomics (total, histone, and phospho to identify networks and potential mechanisms that mediate BCG induced immunomodulation in macrophages. Histone-focused proteomics and total proteomics were performed at the University of Cape Town (data available via ProteomeXchange with identifier PXD051187), while phosphoproteomics data was retrieved from the ProteomeXchange Repository (identifier PXD013171). We identify several epigenetic mechanisms that may drive BCG-induced training phenotypes. Evidence across the proteomics and histone-focused proteomics data sets pair 6 epigenetic effectors (NuA4, NuRD, NSL, Sin3A, SIRT2, SIRT6) and their substrates.
    DOI:  https://doi.org/10.1016/j.mcpro.2024.100851
  25. Int J Mol Sci. 2024 Sep 18. pii: 10049. [Epub ahead of print]25(18):
    WISP1 and Macrophage Migration Inhibitory Factor in Respiratory Inflammation: Novel Insights and Therapeutic Potentials for Asthma and COPD.
    Maria-Elpida Christopoulou, Alexios J Aletras, Eleni Papakonstantinou, Daiana Stolz, Spyros S Skandalis.
      Recent advancements highlight the intricate interplay between the extracellular matrix (ECM) and immune responses, notably in respiratory diseases such as asthma and Chronic Obstructive Pulmonary Disease (COPD). The ECM, a dynamic structural framework within tissues, orches-trates a plethora of cellular processes, including immune cell behavior and tissue repair mecha-nisms. WNT1-inducible-signaling pathway protein 1 (WISP1), a key ECM regulator, controls immune cell behavior, cytokine production, and tissue repair by modulating integrins, PI3K, Akt, β-catenin, and mTOR signaling pathways. WISP1 also induces macrophage migration inhibitory factor (MIF) expression via Src kinases and epidermal growth factor receptor (EGFR) activation. MIF, through its wide range of activities, enhances inflammation and tissue restructuring. Rec-ognized for its versatile roles in regulating the immune system, MIF interacts with multiple immune components, such as the NLRP3 inflammasome, thereby sustaining inflammatory pro-cesses. The WISP1-MIF axis potentially unveils complex molecular mechanisms governing im-mune responses and inflammation. Understanding the intricate roles of WISP1 and MIF in the pathogenesis of chronic respiratory diseases such as asthma and COPD could lead to the identi-fication of novel targets for therapeutic intervention to alleviate disease severity and enhance patient outcomes.
    Keywords:  COPD; MIF; WISP1; asthma; extracellular matrix; inflammation; integrin
    DOI:  https://doi.org/10.3390/ijms251810049
  26. Can J Microbiol. 2024 Oct 03.
    Mechanisms and Implications of Phenotypic Switching in Bacterial Pathogens.
    Alexander Stephen Byrne, Nathalie Bissonnette, Kapil Tahlan.
      Bacteria encounter various stressful conditions within a variety of dynamic environments, which they must overcome for survival. One way they achieve this is by developing phenotypic heterogeneity to introduce diversity within their population. Such distinct subpopulations can arise through endogenous fluctuations in regulatory components, wherein bacteria can express diverse phenotypes and switch between them, sometimes in a heritable and reversible manner. This switching may also lead to antigenic variation, enabling pathogenic bacteria to evade the host immune response. Therefore, phenotypic heterogeneity plays a significant role in microbial pathogenesis, immune evasion, antibiotic resistance, host niche tissue establishment and environmental persistence. This heterogeneity can result from stochastic and responsive switches, as well as various genetic and epigenetic mechanisms. The development of phenotypic heterogeneity may create clonal populations that differ in their level of virulence, contribute to the formation of biofilms, and allow for antibiotic persistence within select morphological variants. This review delves into the current understanding of the molecular switching mechanisms underlying phenotypic heterogeneity, highlighting their roles in establishing infections caused by select bacterial pathogens.
    DOI:  https://doi.org/10.1139/cjm-2024-0116
  27. Nat Immunol. 2024 Oct 04.
    Monocyte-derived macrophages are too much of a good thing in lung fibrosis.
    Leif Erik Sander.
      
    DOI:  https://doi.org/10.1038/s41590-024-01989-5
  28. Eur Respir J. 2024 Oct;pii: 2401526. [Epub ahead of print]64(4):
    Salivary polyreactive antibodies, airway bacteria, and recurrent respiratory infection severity.
    Ryohei Shibata, Yoshihiko Raita, Zhaozhong Zhu.
      
    DOI:  https://doi.org/10.1183/13993003.01526-2024
  29. Bull Exp Biol Med. 2024 Sep;177(5): 658-661
    Changes in Innate Immunity and Microbiome in Different Aging Phenotypes.
    L V Gankovskaya, O A Svitich, A V Poddubikov, V V Burmakina, E M Khasanova, S V Gorodishchenskaya.
      The indicators of innate immunity and the composition of the microbiome in the nasopharyngeal mucosa in centenarians with different aging phenotypes were analyzed. A significant increase in the expression of pattern-recognizing receptor genes (TLR2, TLR4, and NLRP3) and proinflammatory cytokines (IL1B, IL18) was shown in the group of centenarians with pathological aging phenotype. In centenarians with successful aging phenotype, increased diversity of the microbiome composition was observed. At the same time, a moderate inverse correlation was found between an increase in the growth of the commensal bacterium Streptococcus salivarius and a decrease in the expression of proinflammatory cytokine genes IL1B and IL18. These findings can serve as biomarkers for the timely identification of the phenotype of aging in senile and elderly people.
    Keywords:  NOD-like receptors; Toll-like receptors; cytokines; inflammaging; microbiome
    DOI:  https://doi.org/10.1007/s10517-024-06244-3
  30. Gut Microbes. 2024 Jan-Dec;16(1):16(1): 2409209
    The role of microbial indole metabolites in tumor.
    Dingjiacheng Jia, Zheng Kuang, Liangjing Wang.
      The gut microbiota can produce a variety of microbial-derived metabolites to influence tumor development. Tryptophan, an essential amino acid in the human body, can be converted by microorganisms via the indole pathway to indole metabolites such as Indole-3-Lactic Acid (ILA), Indole-3-Propionic Acid (IPA), Indole Acetic Acid (IAA) and Indole-3-Aldehyde (IAld). Recent studies have shown that indole metabolites play key roles in tumor progression, and they can be used as adjuvant regimens for tumor immunotherapy or chemotherapy. Here, we summarize recent findings on the common microbial indole metabolites and provide a review of the mechanisms of different indole metabolites in the tumor microenvironment. We further discuss the limitations of current indole metabolite research and future possibilities. It is expected that microbial indole metabolites will provide new strategies for clinical therapy.
    Keywords:  Indole-3-lactic acid; Indole-3-propionic acid; Tryptophan; ferroptosis; gut microbiota; immune checkpoint blockade; indole metabolites; tumor chemotherapy
    DOI:  https://doi.org/10.1080/19490976.2024.2409209
  31. NPJ Biofilms Microbiomes. 2024 Oct 02. 10(1): 99
    Metabolic interactions shape emergent biofilm structures in a conceptual model of gut mucosal bacterial communities.
    Amin Valiei, Andrew Dickson, Javad Aminian-Dehkordi, Mohammad R K Mofrad.
      The gut microbiome plays a major role in human health; however, little is known about the structural arrangement of microbes and factors governing their distribution. In this work, we present an in silico agent-based model (ABM) to conceptually simulate the dynamics of gut mucosal bacterial communities. We explored how various types of metabolic interactions, including competition, neutralism, commensalism, and mutualism, affect community structure, through nutrient consumption and metabolite exchange. Results showed that, across scenarios with different initial species abundances, cross-feeding promotes species coexistence. Morphologically, competition and neutralism resulted in segregation, while mutualism and commensalism fostered high intermixing. In addition, cooperative relations resulted in community properties with little sensitivity to the selective uptake of metabolites produced by the host. Moreover, metabolic interactions strongly influenced colonization success following the invasion of newcomer species. These results provide important insights into the utility of ABM in deciphering complex microbiome patterns.
    DOI:  https://doi.org/10.1038/s41522-024-00572-y
  32. Nat Commun. 2024 Sep 30. 15(1): 8464
    Phosphorylation of caspases by a bacterial kinase inhibits host programmed cell death.
    Jinli Ge, Ying Wang, Xueyu Li, Qian Lu, Hangqian Yu, Hongtao Liu, Kelong Ma, Xuming Deng, Zhao-Qing Luo, Xiaoyun Liu, Jiazhang Qiu.
      The intracellular bacterial pathogen Legionella pneumophila utilizes the Dot/Icm system to translocate over 330 effectors into the host cytosol. These virulence factors modify a variety of cell processes, including pathways involved in cell death and survival, to promote bacterial proliferation. Here, we show that the effector LegK3 is a eukaryotic-like Ser/Thr kinase that functions to suppress host apoptosis. Mechanistically, LegK3 directly phosphorylates multiple caspases involved in apoptosis signaling, including Caspase-3, Caspase-7, and Caspase-9. LegK3-induced phosphorylation of these caspases occurs at serine (Ser29 in Caspase-3 and Ser199 in Caspase-7) or threonine (Thr102 in Caspase-9) residues located in the prodomain or interdomain linkers. These modifications interfere with the suitability of the caspases as the substrates of initiator caspases or upstream regulators without impacting their proteolytic activity. Collectively, our study reveals a novel strategy used by L. pneumophila to maintain the integrity of infected cells for its intracellular growth.
    DOI:  https://doi.org/10.1038/s41467-024-52817-1
  33. Artif Cells Nanomed Biotechnol. 2024 Dec;52(1): 476-499
    In vitro 3D skin culture and its sustainability in toxicology: a narrative review.
    Syafira Masri, Mh Busra Fauzi, Nor Fadilah Rajab, Wing-Hin Lee, Diana Atiqah Zainal Abidin, Ee Ling Siew.
      In current toxicological research, 2D cell cultures and animal models are well- accepted and commonly employed methods. However, these approaches have many drawbacks and are distant from the actual environment in human. To embrace this, great efforts have been made to provide alternative methods for non-animal skin models in toxicology studies with the need for more mechanistically informative methods. This review focuses on the current state of knowledge regarding the in vitro 3D skin model methods, with different functional states that correspond to the sustainability in the field of toxicology testing. We discuss existing toxicology testing methods using in vitro 3D skin models which provide a better understanding of the testing requirements that are needed. The challenges and future landscape in using the in vitro 3D skin models in toxicology testing are also discussed. We are confident that the in vitro 3D skin models application may become an important tool in toxicology in the context of risk assessment.
    Keywords:  3D skin model; Alternative; non-animal; sustainability; toxicology;  vitro testing
    DOI:  https://doi.org/10.1080/21691401.2024.2407617
  34. World J Gastroenterol. 2024 Sep 14. 30(34): 3856-3861
    Overview of ferroptosis and pyroptosis in acute liver failure.
    Ya-Wen Sun, Bo-Wen Zhao, Hai-Fang Li, Guang-Xiao Zhang.
      In this editorial, we comment on the article by Zhou et al published in a recent issue. We specifically focus on the crucial roles of ferroptosis and pyroptosis in acute liver failure (ALF), a disease with high mortality rates. Ferroptosis is the result of increased intracellular reactive oxygen species due to iron accumulation, glutathione (GSH) depletion, and decreased GSH peroxidase 4 activity, while pyroptosis is a procedural cell death mediated by gasdermin D which initiates a sustained inflammatory process. In this review, we describe the characteristics of ferroptosis and pyroptosis, and discuss the involvement of the two cell death modes in the onset and development of ALF. Furthermore, we summarize several interfering methods from the perspective of ferroptosis and pyroptosis for the alleviation of ALF. These observations might provide new targets and a theoretical basis for the treatment of ALF, which are also crucial for improving the prognosis of patients with ALF.
    Keywords:  Acute liver failure; Ferroptosis; Gasdermin D; Glutathione peroxidase 4; Pyroptosis
    DOI:  https://doi.org/10.3748/wjg.v30.i34.3856
  35. Cell Death Discov. 2024 Oct 02. 10(1): 424
    Repair and regeneration: ferroptosis in the process of remodeling and fibrosis in impaired organs.
    Jiali Yin, Xinjun Xu, Ying Guo, Caiyu Sun, Yujuan Yang, Huifang Liu, Pengyi Yu, Tong Wu, Xicheng Song.
      As common clinical-pathological processes, wound healing and tissue remodelling following injury or stimulation are essential topics in medical research. Promoting the effective healing of prolonged wounds, improving tissue repair and regeneration, and preventing fibrosis are important and challenging issues in clinical practice. Ferroptosis, which is characterized by iron overload and lipid peroxidation, is a nontraditional form of regulated cell death. Emerging evidence indicates that dysregulated metabolic pathways and impaired iron homeostasis play important roles in various healing and regeneration processes via ferroptosis. Thus, we review the intrinsic mechanisms of tissue repair and remodeling via ferroptosis in different organs and systems under various conditions, including the inflammatory response in skin wounds, remodeling of joints and cartilage, and fibrosis in multiple organs. Additionally, we summarize the common underlying mechanisms, key molecules, and targeted drugs for ferroptosis in repair and regeneration. Finally, we discuss the potential of therapeutic agents, small molecules, and novel materials emerging for targeting ferroptosis to promote wound healing and tissue repair and attenuate fibrosis.
    DOI:  https://doi.org/10.1038/s41420-024-02181-2
  36. Antibiotics (Basel). 2024 Sep 23. pii: 909. [Epub ahead of print]13(9):
    Clarithromycin Modulates Neutrophilic Inflammation Induced by Prevotella intermedia in Human Airway Epithelial Cells.
    Naoki Iwanaga, Ayaka Ota, Hiroki Ashizawa, Yuya Ito, Tatsuro Hirayama, Masataka Yoshida, Kazuaki Takeda, Shotaro Ide, Masato Tashiro, Naoki Hosogaya, Noriho Sakamoto, Takahiro Takazono, Kosuke Kosai, Mariko Naito, Yoshimasa Tanaka, Kazuhiro Yatera, Koichi Izumikawa, Katsunori Yanagihara, Hiroshi Mukae.
      Objectives: In the present study, we aimed to clarify the mechanisms by which periodontal pathogens, particularly Prevotella intermedia, induce severe neutrophilic inflammation. In addition, we aimed to test the efficacy of macrolides, which has not been resolved in the neutrophilic inflammation induced by P. intermedia. Methods: NCl-H292 human airway epithelial cells were pre-incubated with clarithromycin for 2 h before incubation with P. intermedia supernatants. Then, C-X-C motif chemokine ligand 8 (CXCL8) transcription and interleukin (IL)-8 production were measured. To elucidate the signaling pathway, mitogen-activated protein kinase inhibitors were added to the cell culture, and the cells were subjected to Western blotting. Results:P. intermedia supernatants promoted CXCL8 transcription and IL-8 production, and the reactions were significantly suppressed by clarithromycin pretreatment. Only trametinib, the selective mitogen-activated extracellular signal-regulated kinase inhibitor, downregulated CXCL8 transcription and IL-8 production. Furthermore, Western blotting revealed that stimulation with P. intermedia supernatants specifically induces extracellular signal-regulated kinases (ERK) 1/2 phosphorylation, which is suppressed by clarithromycin pretreatment. Notably, the interference analysis revealed that ERK3 might be dispensable for IL-8 production under the stimulation of P. intermedia supernatants. Conclusions: Our results provide new insight into the mechanism underlying P. intermedia-induced production of IL-8 from human airway epithelial cells. Furthermore, macrolides might have therapeutic potential in regulating periodontal pathogen-induced neutrophilic inflammation in the lungs.
    Keywords:  Prevotella intermedia; clarithromycin; human airway epithelial cells
    DOI:  https://doi.org/10.3390/antibiotics13090909
  37. Vet Res. 2024 Sep 27. 55(1): 120
    RACK1 and NEK7 mediate GSDMD-dependent macrophage pyroptosis upon Streptococcus suis infection.
    Xin Shen, Jinrong Ran, Qingqing Yang, Bingjie Li, Yi Lu, Jiajia Zheng, Liuyi Xu, Kaixiang Jia, Zhiwei Li, Lianci Peng, Rendong Fang.
      Streptococcus suis serotype 2 (SS2) is an important zoonotic pathogen that induces an NLRP3-dependent cytokine storm. NLRP3 inflammasome activation triggers not only an inflammatory response but also pyroptosis. However, the exact mechanism underlying S. suis-induced macrophage pyroptosis is not clear. Our results showed that SS2 induced the expression of pyroptosis-associated factors, including lactate dehydrogenase (LDH) release, propidium iodide (PI) uptake and GSDMD-N expression, as well as NLRP3 inflammasome activation and IL-1β secretion. However, GSDMD deficiency and NLRP3 inhibition using MCC950 attenuated the SS2-induced expression of pyroptosis-associated factors, suggesting that SS2 induces NLRP3-GSDMD-dependent pyroptosis. Furthermore, RACK1 knockdown also reduced the expression of pyroptosis-associated factors. In addition, RACK1 knockdown downregulated the expression of NLRP3 and Pro-IL-1β as well as the phosphorylation of P65. Surprisingly, the interaction between RACK1 and P65 was detected by co-immunoprecipitation, indicating that RACK1 induces macrophage pyroptosis by mediating the phosphorylation of P65 to promote the transcription of NLRP3 and pro-IL-1β. Similarly, NEK7 knockdown decreased the expression of pyroptosis-associated factors and ASC oligomerization. Moreover, the results of co-immunoprecipitation revealed the interaction of NEK7-RACK1-NLRP3 during SS2 infection, demonstrating that NEK7 mediates SS2-induced pyroptosis via the regulation of NLRP3 inflammasome assembly and activation. These results demonstrate the important role of RACK1 and NEK7 in SS2-induced pyroptosis. Our study provides new insight into SS2-induced cell death.
    Keywords:   Streptococcus suis ; GSDMD; NEK7; NLRP3 inflammasome; RACK1; pyroptosis
    DOI:  https://doi.org/10.1186/s13567-024-01376-w
  38. J Leukoc Biol. 2024 Sep 28. pii: qiae211. [Epub ahead of print]
    Immunometabolic Chaos in Septic Shock.
    Deepmala Shrestha, Bishnu Pant, Sanjoy Roychowdhury, Anugraha Gandhirajan, Emily Cross, Mamta Chhabria, Seth Bauer, Margaret Jeng, Megan Mitchell, Omar Mehkri, Fatima Zaidi, Akash Ahuja, Xiaofeng Wang, Yuxin Wang, Christine McDonald, Michelle Longworth, Thaddeus Stappenbeck, George R Stark, Rachel Scheraga, Vidula Vachharajani.
      Septic shock is associated with over 40% mortality. The immune response in septic shock is tightly regulated by cellular metabolism and transitions from early hyper-inflammation to later hypo-inflammation. Patients are susceptible to secondary infections during hypo-inflammation. The magnitude of the metabolic dysregulation and the effect of plasma metabolites on the circulating immune cells in septic shock are not reported. We hypothesized that the accumulated plasma metabolites affect the immune response in septic shock during hypo-inflammation. Our study took a unique approach. Using peripheral blood from adult septic shock patients and healthy controls, we studied: 1. Whole blood stimulation ± E. Coli lipopolysaccharide (LPS: endotoxin) to analyze plasma TNF protein, and 2. Plasma metabolomic profile by Metabolon. Inc. 3. We exposed peripheral blood mononuclear cells (PBMCs) from healthy controls to commercially available carbohydrate, amino acid, and fatty acid metabolites and studied the response to LPS. We report that: 1. The whole blood stimulation of the healthy control group showed a significantly upregulated TNF protein, while the septic shock group remained endotoxin tolerant, a biomarker for hypo-inflammation. 2. A significant accumulation of carbohydrate, amino acid, fatty acid, ceramide, sphingomyelin, and TCA cycle pathway metabolites in septic shock plasma. 3. In vitro exposure to five metabolites repressed while two metabolites upregulated the inflammatory response of PBMCs to LPS. We conclude that the endotoxin-tolerant phenotype of septic shock is associated with a simultaneous accumulation of plasma metabolites from multiple metabolic pathways, and these metabolites fundamentally influence the immune response profile of circulating cells.
    Keywords:  Metabolism; Monocytes; Sepsis; Septic shock
    DOI:  https://doi.org/10.1093/jleuko/qiae211
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