GPR81, a cell-surface receptor for lactate, regulates intestinal homeostasis and protects mice from experimental colitis

Punithavathi Ranganathan, Arul Kumaran Shanmugam, Daniel Swafford, Amol Suryawanshi, Pushpak Bhattacharjee, Mohamed S. Hussein, Pandelakis Koni, Puttur D Prasad, Zoya Bronislavovna Kurago, Muthusamy Thangaraju, Vadivel Ganapathy, Santhakumar Manicassamy

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

At mucosal sites such as the intestine, the immune system launches robust immunity against invading pathogens while maintaining a state of tolerance to commensal flora and ingested food Ags. The molecular mechanisms underlying this phenomenon remain poorly understood. In this study, we report that signaling by GPR81, a receptor for lactate, in colonic dendritic cells and macrophages plays an important role in suppressing colonic inflammation and restoring colonic homeostasis. Genetic deletion of GPR81 in mice led to increased Th1/Th17 cell differentiation and reduced regulatory T cell differentiation, resulting in enhanced susceptibility to colonic inflammation. This was due to increased production of proinflammatory cytokines (IL-6, IL-1β, and TNF-α) and decreased expression of immune regulatory factors (IL-10, retinoic acid, and IDO) by intestinal APCs lacking GPR81. Consistent with these findings, pharmacological activation of GPR81 decreased inflammatory cytokine expression and ameliorated colonic inflammation. Taken together, these findings identify a new and important role for the GPR81 signaling pathway in regulating immune tolerance and colonic inflammation. Thus, manipulation of the GPR81 pathway could provide novel opportunities for enhancing regulatory responses and treating colonic inflammation.

Original languageEnglish (US)
Pages (from-to)1781-1789
Number of pages9
JournalJournal of Immunology
Volume200
Issue number5
DOIs
StatePublished - Mar 1 2018

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Cell Surface Receptors
Colitis
Lactic Acid
Homeostasis
Inflammation
Cell Differentiation
Cytokines
Th17 Cells
Immune Tolerance
Th1 Cells
Immunologic Factors
Regulatory T-Lymphocytes
Tretinoin
Interleukin-1
Interleukin-10
Dendritic Cells
Intestines
Immune System
Immunity
Interleukin-6

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

GPR81, a cell-surface receptor for lactate, regulates intestinal homeostasis and protects mice from experimental colitis. / Ranganathan, Punithavathi; Shanmugam, Arul Kumaran; Swafford, Daniel; Suryawanshi, Amol; Bhattacharjee, Pushpak; Hussein, Mohamed S.; Koni, Pandelakis; Prasad, Puttur D; Kurago, Zoya Bronislavovna; Thangaraju, Muthusamy; Ganapathy, Vadivel; Manicassamy, Santhakumar.

In: Journal of Immunology, Vol. 200, No. 5, 01.03.2018, p. 1781-1789.

Research output: Contribution to journalArticle

Ranganathan P, Shanmugam AK, Swafford D, Suryawanshi A, Bhattacharjee P, Hussein MS et al. GPR81, a cell-surface receptor for lactate, regulates intestinal homeostasis and protects mice from experimental colitis. Journal of Immunology. 2018 Mar 1;200(5):1781-1789. https://doi.org/10.4049/jimmunol.1700604
Ranganathan, Punithavathi ; Shanmugam, Arul Kumaran ; Swafford, Daniel ; Suryawanshi, Amol ; Bhattacharjee, Pushpak ; Hussein, Mohamed S. ; Koni, Pandelakis ; Prasad, Puttur D ; Kurago, Zoya Bronislavovna ; Thangaraju, Muthusamy ; Ganapathy, Vadivel ; Manicassamy, Santhakumar. / GPR81, a cell-surface receptor for lactate, regulates intestinal homeostasis and protects mice from experimental colitis. In: Journal of Immunology. 2018 ; Vol. 200, No. 5. pp. 1781-1789.
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