TY - JOUR
T1 - Gpr109a limits microbiota-induced IL-23 production to constrain ILC3-mediated colonic inflammation
AU - Bhatt, Brinda
AU - Zeng, Peng
AU - Zhu, Huabin
AU - Sivaprakasam, Sathish
AU - Li, Siyi
AU - Xiao, Haiyan
AU - Dong, Lixin
AU - Shiao, Shyang-Yun Pamela
AU - Kolhe, Ravindra Bharat
AU - Li, Honglin
AU - Levy Bercowski, Daniel
AU - Ganapathy, Vadivel
AU - Singh, Nagendra
AU - Patel, Nikhil
N1 - Funding Information:
This work was supported by National Institutes of Health Grant R01DK103576 to N.S.
Publisher Copyright:
Copyright © 2018 by The American Association of Immunologists, Inc.
PY - 2018/4/15
Y1 - 2018/4/15
N2 - 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 2 / 2 Rag1 2 / 2 mice exhibit spontaneous rectal prolapse and colonic inflammation, characterized by the presence of an elevated number of IL-17–producing Rorgt + innate lymphoid cells (ILCs; ILC3). Genetic deletion of Rorgt alleviated the spontaneous colonic inflammation in Gpr109a 2 / 2 Rag1 2 / 2 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 2 / 2 Rag1 2 / 2 mice. The ceca of Gpr109a 2 / 2 Rag1 2 / 2 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 2 / 2 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.
AB - 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 2 / 2 Rag1 2 / 2 mice exhibit spontaneous rectal prolapse and colonic inflammation, characterized by the presence of an elevated number of IL-17–producing Rorgt + innate lymphoid cells (ILCs; ILC3). Genetic deletion of Rorgt alleviated the spontaneous colonic inflammation in Gpr109a 2 / 2 Rag1 2 / 2 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 2 / 2 Rag1 2 / 2 mice. The ceca of Gpr109a 2 / 2 Rag1 2 / 2 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 2 / 2 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.
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U2 - 10.4049/jimmunol.1701625
DO - 10.4049/jimmunol.1701625
M3 - Article
C2 - 29514953
AN - SCOPUS:85046766590
SN - 0022-1767
VL - 200
SP - 2905
EP - 2914
JO - Journal of Immunology
JF - Journal of Immunology
IS - 8
ER -