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Gpr109a Limits Microbiota-Induced IL-23 Production To Constrain ILC3-Mediated Colonic Inflammation.


ABSTRACT: A set of coordinated interactions between gut microbiota and the immune cells surveilling the intestine play a key role in shaping local immune responses and intestinal health. Gpr109a is a G protein-coupled receptor expressed at a very high level on innate immune cells and previously shown to play a key role in the induction of colonic regulatory T cells. In this study, we show that Gpr109a-/-Rag1-/- mice exhibit spontaneous rectal prolapse and colonic inflammation, characterized by the presence of an elevated number of IL-17-producing Ror?t+ innate lymphoid cells (ILCs; ILC3). Genetic deletion of Ror?t alleviated the spontaneous colonic inflammation in Gpr109a-/-Rag1-/- mice. Gpr109a-deficient colonic dendritic cells produce higher amounts of IL-23 and thereby promote ILC3. Moreover, the depletion of gut microbiota by antibiotics treatment decreased IL-23 production, ILC3, and colonic inflammation in Gpr109a-/-Rag1-/- mice. The ceca of Gpr109a-/-Rag1-/- mice showed significantly increased colonization by members of Bacteroidaceae, Porphyromonadaceae, Prevotellaceae, Streptococcaceae, Christensenellaceae, and Mogibacteriaceae, as well as IBD-associated microbiota such as Enterobacteriaceae and Mycoplasmataceae, compared with Rag1-/- mice, housed in a facility positive for Helicobacter and murine norovirus. Niacin, a Gpr109a agonist, suppressed both IL-23 production by colonic DCs and ILC3 number in a Gpr109a-dependent manner. Collectively, our data present a model suggesting that targeting Gpr109a will be potentially beneficial in the suppression of IL-23-mediated immunopathologies.

SUBMITTER: Bhatt B 

PROVIDER: S-EPMC5893356 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Gpr109a Limits Microbiota-Induced IL-23 Production To Constrain ILC3-Mediated Colonic Inflammation.

Bhatt Brinda B   Zeng Peng P   Zhu Huabin H   Sivaprakasam Sathish S   Li Siyi S   Xiao Haiyan H   Dong Lixin L   Shiao Pamela P   Kolhe Ravindra R   Patel Nikhil N   Li Honglin H   Levy-Bercowski Daniel D   Ganapathy Vadivel V   Singh Nagendra N  

Journal of immunology (Baltimore, Md. : 1950) 20180307 8


A set of coordinated interactions between gut microbiota and the immune cells surveilling the intestine play a key role in shaping local immune responses and intestinal health. Gpr109a is a G protein-coupled receptor expressed at a very high level on innate immune cells and previously shown to play a key role in the induction of colonic regulatory T cells. In this study, we show that <i>Gpr109a<sup>-/-</sup>Rag1<sup>-/-</sup></i> mice exhibit spontaneous rectal prolapse and colonic inflammation,  ...[more]

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