Immunity Ruan Haibin's research group discovered a new molecular mechanism of intestinal antiparasitic immunity

Editor-in-Chief | About 1.
5 billion people in the world are still suffering from worm infections
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In recent years, a series of studies have found that after helminth infection, the intestinal epithelial layer will activate the intestine by increasing the differentiation of goblet cells and tuft cells and the secretion of "alarms" interleukins-25 and 33.
Type 2 immune responses within tissues and kill and eliminate pathogenic microorganisms
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At the same time, dysregulation of the type 2 immune response is also responsible for the high incidence of autoimmune and allergic diseases in developed countries
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However, the activation and regulation mechanism of intestinal type 2 immune response at the molecular level is not fully understood
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On April 5, 2022, Haibin Ruan's group at the University of Minnesota published the research results of Epithelial STAT6 O-GlcNAcylation drives a concerted anti-helminth alarmin response dependent on tuft cell hyperplasia and Gasdermin C in Immunity
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This study reveals that O-acetylglycosamine modification of STAT6 transcription factor (O-GlcNAc)-mediated expression of Pou2f3 and Gasdermin C (GSDMC) in intestinal epithelial cells is important for cluster cell proliferation and increased interleukin-33 secretion, respectively mechanism
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This in turn is the basis for activating type 2 innate immune cells and T helper cells to form a positive feedback activation loop of intestinal type 2 immune response
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Professor Haibin Ruan's group has previously conducted a series of explorations on the role of O-acetylglucosamine modification in immune and metabolic regulation in immune cells and intestinal epithelial cells.
This study is a further exploration on the basis of previous research
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In this study, the authors first found that intestinal worm infection can significantly increase the level of protein O-acetylglucosamine modification in the gut
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The intestinal epithelium-specific knockout of O-acetylglucosamine-modified mice lost the immune response against helminth infection, including the proliferation of tuft cells and goblet cells and the expression of various cytokines
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Further experiments in which O-acetylglucosamine modification was knocked out in mouse mature tuft cells and intestinal stem cells respectively confirmed that the main role of O-acetylglucosamine modification was to regulate the differentiation of intestinal stem cells into different mature cells
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Since the STAT6 transcription factor regulates the differentiation of intestinal stem cells into tuft cells, the authors focused on the regulation of STAT6 by O-acetylglucosamine modification
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By means of liquid chromatography, the authors discovered multiple O-acetylglucosamine modification sites on STAT6
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Then, the authors confirmed that the O-acetylglucosamine modification of STAT6 can regulate the expression of the tuft cell regulator Pou2f3 independently of the phosphorylation modification at the Y641 site by a series of gene editing methods in intestinal epithelial organoids, and then affect the tuft cells.
Differentiation and secretion of IL-25
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After helminth infection, the intestinal epithelium increases the secretion of interleukin-33 (IL-33) to activate type 2 innate immune cells and T helper cells in addition to the secretion of tuft cells and the "alarm" IL-25
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However, due to the lack of a signal peptide for secretion, IL-33 is not secreted through the Golgi pathway, and the active secretion regulation mechanism of IL-33 has not been elucidated
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In this study, the authors found that O-acetylglucosamine modification of STAT6 could significantly increase the expression of GSDMC
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The N-segment polymer of GSDMC protein (GSDMCN) can punch holes in the cell membrane, mediate IL-33 secretion and resist helminth infection
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Interestingly, enteritis was accompanied by overexpression of GSDMC, and GSDMC knockout mice were resistant to DSS and IL-10 knockout-induced enteritis
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This study is the first to elucidate the non-pyroptotic mechanism and physiological role of the little-studied GSDMC protein in the Gasdermin family
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In conclusion, through a series of transgenic animal models, organoid culture and molecular biology research methods, this study found that the O-acetylglucosamine modification of STAT6 is an important molecular signal for inducing intestinal epithelial antihelminthic type II immune response.

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It activates type 2 inflammation and clears worms by increasing cluster cell differentiation and GSDMC expression, coordinating the secretion of two "alarms", IL-25 and IL-33
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These findings not only expand the therapeutic idea of ​​anti-parasitic infection, but also provide new intervention targets for other diseases related to dysregulated type 2 immune response
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Dr.
Zhao Ming from the University of Minnesota is the first author of this article, and Professor Ruan Haibin from the University of Minnesota and Professor Lin Zhaoyu from Nanjing University are the co-corresponding authors of this article
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The research groups of Professor Ren Kaiqun and Professor Xiong Xiwen are also important participants in the paper
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Currently, the research group of Ruan Haibin at the University of Minnesota is recruiting a postdoctoral fellow (immunometabolism)
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org/10.
1016/j.
immuni.
2022.
03.
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