title: Homeostatic PPARα Signaling Limits Inflammatory Responses to Commensal Microbiota in the Intestine.
abstract: Dietary lipids and their metabolites activate members of the peroxisome proliferative-activated receptor (PPAR) family of transcription factors and are critical for colonic health. The PPARα isoform plays a vital role in regulating inflammation in various disease settings, but its role in intestinal inflammation, commensal homeostasis, and mucosal immunity in the gut are unclear. In this study, we demonstrate that the PPARα pathway in innate immune cells orchestrates gut mucosal immunity and commensal homeostasis by regulating the expression of IL-22 and the antimicrobial peptides RegIIIβ, RegIIIγ, and calprotectin. Additionally, the PPARα pathway is critical for imparting regulatory phenotype in intestinal macrophages. PPARα deficiency in mice led to commensal dysbiosis in the gut, resulting in a microbiota-dependent increase in the expression of inflammatory cytokines and enhanced susceptibility to intestinal inflammation. Pharmacological activation of this pathway decreased the expression of inflammatory cytokines and ameliorated colonic inflammation. Taken together, these findings identify a new important innate immune function for the PPARα signaling pathway in regulating intestinal inflammation, mucosal immunity, and commensal homeostasis. Thus, the manipulation of the PPARα pathway could provide novel opportunities for enhancing mucosal immunity and treating intestinal inflammation.
authors.affiliation: Cancer Center, Augusta University, Augusta, GA 30912;
authors.forename: Indumathi
authors.initials: I
authors.lastname: Manoharan
authors.affiliation: Cancer Center, Augusta University, Augusta, GA 30912;
authors.forename: Amol
authors.initials: A
authors.lastname: Suryawanshi
authors.affiliation: Cancer Center, Augusta University, Augusta, GA 30912;
authors.forename: Yuan
authors.initials: Y
authors.lastname: Hong
authors.affiliation: Cancer Center, Augusta University, Augusta, GA 30912;
authors.forename: Punithavathi
authors.initials: P
authors.lastname: Ranganathan
authors.affiliation: Cancer Center, Augusta University, Augusta, GA 30912;
authors.forename: Arulkumaran
authors.initials: A
authors.lastname: Shanmugam
authors.affiliation: Cancer Center, Augusta University, Augusta, GA 30912;
authors.forename: Shamim
authors.initials: S
authors.lastname: Ahmad
authors.affiliation: Cancer Center, Augusta University, Augusta, GA 30912;
authors.forename: Daniel
authors.initials: D
authors.lastname: Swafford
authors.affiliation: Department of Microbiology, University of Chicago, Chicago, IL 60637;
authors.forename: Balaji
authors.initials: B
authors.lastname: Manicassamy
authors.affiliation: Vascular Biology Center, Augusta University, Augusta, GA 30912;
authors.forename: Ganesan
authors.identifier: 0000-0002-8968-0721
authors.initials: G
authors.lastname: Ramesh
authors.affiliation: Cancer Center, Augusta University, Augusta, GA 30912; Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912; and.
authors.forename: Pandelakis A
authors.initials: PA
authors.lastname: Koni
authors.affiliation: Cancer Center, Augusta University, Augusta, GA 30912; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912.
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Thangaraju
authors.affiliation: Cancer Center, Augusta University, Augusta, GA 30912; Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912; and Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912 smanicassamy@gru.edu.
authors.forename: Santhakumar
authors.identifier: 0000-0002-2203-3917
authors.initials: S
authors.lastname: Manicassamy
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D000069196:Gastrointestinal Microbiome / Q000276:immunology*; D018398:Homeodomain Proteins / Q000276:immunology; D006706:Homeostasis; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047493:PPAR alpha / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018398:Homeodomain Proteins; D047493:PPAR alpha; C064658:RAG-1 protein