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Principal Investigator: Ivan Zanoni
Organization: BOSTON CHILDREN'S HOSPITAL
Fiscal Year: 2024
Award: $646,238
Funding agency: National Institute of Allergy and Infectious Diseases
Inflammation evolved to lead to recovery from sterile or microbial injuries. The induction of the inflammatory process not only activates the immune cells, but also alters their metabolism and thus forge the immune response. Accumulating evidence shows that a proper inflammatory process requires the coincident recognition by pattern recognition receptors (PRRs) of exogenous pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs). We recently demonstrated that the coincident recognition of lipopolysaccharide (LPS), the major component of Gram-negative bacteria, and host-derived oxidized phospholipids known as oxPAPC (a class of DAMPs) leads to the formation of phagocytes characterized by a unique metabolic profile that increases the production of interleukin (IL)-1β, a potent pro-inflammatory cytokine. Whether, and how, the simultaneous encounter of LPS and oxPAPC alters other inflammatory activities of phagocytes remains largely unknown. Based on new compelling data, here we hypothesize that the coincident recognition of LPS and oxPAPC alters key metabolic checkpoints to drive hyper-inflammation. Also, that these changes can be harnessed against septic shock. Sepsis is a complex inflammatory syndrome characterized by a hyper-inflammatory phase called septic shock. Although it was previously proposed that oxPAPC protects against the hyperinflammatory phase of sepsis by inhibiting the capacity of LPS to signal, our new unpublished data show instead that oxPAPC production follows LPS or bacterial encounter in vivo and that oxPAPC increases inflammation and lethality in mouse models of sepsis. Notably, we found that, to exert its functions, oxPAPC directly interacts with, and inhibits, AKT. AKT is a central metabolic checkpoint that regulates the metabolism of phagocytes and their inflammatory activity. AKT inhibition by oxPAPC prevents the production of IL-10. IL-10 is a pluripotent immunoregulatory cytokine indispensable for maintaining immune homeostasis and restricting inflammation during sepsis. Mechanistically, oxPAPC-dependent inhibition of AKT potentiates the methionine cycle and favors the trimethylation of the histone H3, thus switching off IL-10 transcription. Supported by our new solid data, we will employ biochemistry, transcriptional and epigenetic analyses, as well as metabolomics in vitro to further dissect the signaling cascade initiated by oxPAPC during LPS encounter. By using new transgenic or conditional knock-out mice, as well as commercially available drugs, we will test in vivo the possibility to target the newly identified metabolic pathways regulated by oxPAPC to protect against sepsis. Altogether we will characterize the molecular components that mediate host-derived inflammatory ligand-dependent immunometabolic functions. Our study will offer potential therapeutic targets for modulating immune system activation and sepsis, a devastating inflammatory syndrome that is widespread in western countries.
Terms: <AKT><AKT inhibition><Affect><Akt protein><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Autoregulation><Bacteremia><Beta Proprotein Interleukin 1><Binding><Biochemistry><Biological Chemistry><CSIF><CSIF-10><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cessation of life><Choline Chloride Dihydrogen Phosphate><Choline Phosphate><Choline Phosphate Chloride><Complex><Country><Cytokine Synthesis Inhibitory Factor><Data><Death><Development><Drugs><ENX-1><EZH1><EZH2><EZH2 gene><Endotoxic Shock><Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit><Environment><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Equilibrium><Extracellular Space><FDA approved><Gene Transcription><Genes><Genetic Transcription><Goals><Gram-Negative Bacteria><Histone H3><Homeostasis><Human><IL-1 beta><IL-1 β><IL-1-b><IL-10><IL-1β><IL1-Beta><IL1-β><IL10><IL10A><IL1B Protein><IL1F2><IL1β><Immune><Immune response><Immune system><Immunes><Immunological response><Immunomodulation><In Vitro><In vivo analysis><Inflammasome><Inflammation><Inflammatory><Injury><Innate Immune System><Intercellular Space><Interleukin 10 Precursor><Interleukin 1beta><Interleukin-1 beta><Interleukin-10><Interleukin-1β><Intermediary Metabolism><Intervention><Intervention Strategies><Intracellular Communication and Signaling><KMT6><KMT6A><KO mice><Knock-out Mice><Knockout Mice><L-Lysine><Ligands><Lipopolysaccharides><Lysine><Macrophage><Mediating><Medication><Metabolic><Metabolic Pathway><Metabolic Processes><Metabolism><Methionine><Mice><Mice Mammals><Mitochondria><Modern Man><Modification><Molecular><Molecular Interaction><Murine><Mus><Mφ><Null Mouse><Ox-PAPC><Pathology><Pattern><Pattern Recognition><Pattern recognition receptor><Phagocytes><Phagocytic Cell><Pharmaceutical Preparations><Phase><Phosphatides><Phosphocholine><Phospholipids><Phosphorylcholine><Phosphorylcholine Chloride><Physiological Homeostasis><Play><Preinterleukin 1 Beta><Process><Production><Protein Kinase B><Proto-Oncogene Proteins c-akt><RAC-PK protein><RNA Expression><Recovery><Role><Sepsis><Septic Shock><Signal Transduction><Signal Transduction Systems><Signaling><Site><Solid><Sterility><Syndrome><Testing><Therapeutic><Therapeutic Intervention><Transcription><Transgenic Organisms><Work><amebocyte><bacteraemia><bacterial sepsis><balance><balance function><biological signal transduction><blood infection><bloodstream infection><c-akt protein><conditional knock-out><conditional knockout><cytokine><developmental><drug/agent><empowerment><enzyme activity><epigenetically><epigenomics><forging><histone methylation><host response><immune modulation><immune regulation><immune system response><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><in vivo><in vivo evaluation><in vivo testing><injuries><injury to tissue><innovate><innovation><innovative><intervention therapy><interventional strategy><metabolic profile><metabolism measurement><metabolomics><metabonomics><microbial><mitochondrial><mouse model><murine model><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><oxidation><oxidized phosphatidyl choline><pathogen><polymicrobial sepsis><prevent><preventing><proto-oncogene protein RAC><proto-oncogene protein akt><rac protein kinase><related to A and C-protein><social role><sterile><therapeutic target><therapeutically effective><tissue injury><transgenic>