Investigating the lipid-immune signaling axis in modulating the inflammatory response to <i>Salmonella enterica</i>serovar Typhimurium infections

Abstract Salmonella entericaserovar Typhimurium (STM) is an intracellular pathogen that causes gastroenteritis and can disseminate systemically through survival in phagocytes. Eicosanoids-derived bioactive lipids play critical roles both the induction resolution of inflammation during bacterial infections or other insults. A subset these are endogenous ligands for nuclear receptors/transcription factors Peroxisome proliferator-activated receptors (PPAR), which major fatty acid metabolism modulation immune functions (including macrophage MΦ polarization). To elucidate role PPARα, we infected streptomycin-pretreated C57BL/6 (wildtype) Ppara−/−mice with STM (colitis model). We determined have increased eicosanoid production, decreased inflammatory gene expression histopathology scores cecal tissue, reduced systemic dissemination bacteria, compared to mice. These data suggest activation PPARα results a deleterious response favoring infection. When polarizing various subsets, infection enhanced M2b M2c polarizations (anti-inflammatory immunoregulatory) PPARα-dependent manner. Using liquid chromatography-mass spectrometry (LC/MS), also alters profiles polarized MΦ. Specifically, M2b-polarized STM-infected ceramide levels uninfected control, would inhibit programmed cell death enhance survival. findings provide important insights into how reprogramming affects host-pathogen interactions infections. This work was supported by National Institute Allergy Infectious Disease R01 AI168550 (VT)