Homeostatic PPARa signaling limits inflammatory responses to commensal microbiota in the intestine

Indumathi Manoharan, Amol Suryawanshi, Yuan Hong, Punithavathi Ranganathan, Arul Kumaran Shanmugam, Shamim Ahmad, Daniel Swafford, Balaji Manicassamy, Ganesan Ramesh, Pandelakis Koni, Muthusamy Thangaraju, Santhakumar Manicassamy

Research output: Contribution to journalArticle

17 Scopus citations

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 PPARa 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 PPARa pathway in innate immune cells orchestrates gut mucosal immunity and commensal homeostasis by regulating the expression of IL-22 and the antimicrobial peptides RegIIIb, RegIIIg, and calprotectin. Additionally, the PPARa pathway is critical for imparting regulatory phenotype in intestinal macrophages. PPARa 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 PPARa signaling pathway in regulating intestinal inflammation, mucosal immunity, and commensal homeostasis. Thus, the manipulation of the PPARa pathway could provide novel opportunities for enhancing mucosal immunity and treating intestinal inflammation.

Original languageEnglish (US)
Pages (from-to)4739-4749
Number of pages11
JournalJournal of Immunology
Volume196
Issue number11
DOIs
StatePublished - Jun 1 2016

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Manoharan, I., Suryawanshi, A., Hong, Y., Ranganathan, P., Shanmugam, A. K., Ahmad, S., Swafford, D., Manicassamy, B., Ramesh, G., Koni, P., Thangaraju, M., & Manicassamy, S. (2016). Homeostatic PPARa signaling limits inflammatory responses to commensal microbiota in the intestine. Journal of Immunology, 196(11), 4739-4749. https://doi.org/10.4049/jimmunol.1501489