Sunday, May 18, 2025
5/18/2025
Macrophage immunometabolism controls septic shock - 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that oxPAPC protects against the hyperinflammatory phase of sepsis by inhibiting the capacity of LPS to signal, our new unpublished data show instead that oxPAPC production follows LPS or bacterial encounter in vivo and that oxPAPC increases inflammation and lethality in mouse models of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.
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