Remodelling of the gut microbiota by hyperactive NLRP3 induces regulatory T cells to maintain homeostasis

Xiaomin Yao, Chenhong Zhang, Yue Xing, Guang Xue, Qianpeng Zhang, Fengwei Pan, Guojun Wu, Yingxin Hu, Qiuhong Guo, Ailing Lu, Xiaoming Zhang, Rongbin Zhou, Zhigang Tian, Benhua Zeng, Hong Wei, Warren Strober, Liping Zhao () and Guangxun Meng ()
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Xiaomin Yao: Institut Pasteur of Shanghai, Chinese Academy of Sciences; University of Chinese Academy of Sciences
Chenhong Zhang: Department of Biological Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University
Yue Xing: Institut Pasteur of Shanghai, Chinese Academy of Sciences; University of Chinese Academy of Sciences
Guang Xue: Institut Pasteur of Shanghai, Chinese Academy of Sciences; University of Chinese Academy of Sciences
Qianpeng Zhang: Department of Biological Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University
Fengwei Pan: Department of Biological Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University
Guojun Wu: Department of Biological Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University
Yingxin Hu: Department of Biological Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University
Qiuhong Guo: Institut Pasteur of Shanghai, Chinese Academy of Sciences; University of Chinese Academy of Sciences
Ailing Lu: Institut Pasteur of Shanghai, Chinese Academy of Sciences; University of Chinese Academy of Sciences
Xiaoming Zhang: Institut Pasteur of Shanghai, Chinese Academy of Sciences; University of Chinese Academy of Sciences
Rongbin Zhou: School of Life Sciences, University of Science and Technology of China
Zhigang Tian: School of Life Sciences, University of Science and Technology of China
Benhua Zeng: College of Basic Medical Sciences, Third Military Medical University
Hong Wei: College of Basic Medical Sciences, Third Military Medical University
Warren Strober: Laboratory for Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Liping Zhao: Department of Biological Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University
Guangxun Meng: Institut Pasteur of Shanghai, Chinese Academy of Sciences; University of Chinese Academy of Sciences

Nature Communications, 2017, vol. 8, issue 1, 1-17

Abstract: Abstract Inflammasomes are involved in gut homeostasis and inflammatory pathologies, but the role of NLRP3 inflammasome in these processes is not well understood. Cryopyrin-associated periodic syndrome (CAPS) patients with NLRP3 mutations have autoinflammation in skin, joints, and eyes, but not in the intestine. Here we show that the intestines of CAPS model mice carrying an Nlrp3 R258W mutation maintain homeostasis in the gut. Additionally, such mice are strongly resistant to experimental colitis and colorectal cancer; this is mainly through a remodelled gut microbiota with enhanced anti-inflammatory capacity due to increased induction of regulatory T cells (Tregs). Mechanistically, NLRP3R258W functions exclusively in the lamina propria mononuclear phagocytes to directly enhance IL-1β but not IL-18 secretion. Increased IL-1β boosts local antimicrobial peptides to facilitate microbiota remodelling. Our data show that NLRP3R258W-induced remodelling of the gut microbiota, induces local Tregs to maintain homeostasis and compensate for otherwise-detrimental intestinal inflammation.

Date: 2017
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DOI: 10.1038/s41467-017-01917-2

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