Faculty Opinions recommendation of Activation of intestinal tuft cell-expressed Sucnr1 triggers type 2 immunity in the mouse small intestine.

SummaryInitiation of immune responses requires innate immune sensing, but immune detection of the helminths, protists, and allergens that stimulate type 2 immunity remains poorly understood. In the small intestine, type 2 immune responses are regulated by a tuft cell-ILC2 signaling circuit. Tuft cells express components of a canonical taste transduction pathway, including the membrane channel TRPM5, but the ligands and receptors that activate tuft cells in the small intestine are unknown. Here we identify succinate as the first ligand that activates intestinal tuft cells to initiate type 2 immune responses. Using mRNA-Seq on tuft cells from different tissues, we show that all tuft cells express the intracellular taste transduction pathway, but expression of upstream receptors is tissue-specific. In the small intestine, tuft cells express the succinate receptor SUCNR1. Remarkably, providing succinate in drinking water is sufficient to induce a multifaceted type 2 immune response in the murine small intestine, involving all known components of the tuft-ILC2 circuit. The helminthNippostrongylus brasiliensissecretes succinate as a metabolite, and sensing of both succinate andN. brasiliensisrequires tuft cells and TRPM5, suggesting a novel paradigm in which type 2 immunity monitors microbial metabolism. Manipulation of succinate sensing may have therapeutic benefit in numerous intestinal diseases.

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Mitochondrial transcription factor A in RORγt+ lymphocytes regulate small intestine homeostasis and metabolism

Nature Communications ◽

10.1038/s41467-021-24755-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Zheng Fu ◽

Joseph W. Dean ◽

Lifeng Xiong ◽

Michael W. Dougherty ◽

Kristen N. Oliff ◽

...

Keyword(s):

Transcription Factor ◽

Small Intestine ◽

Th17 Cells ◽

Tissue Remodeling ◽

Mitochondrial Transcription ◽

Mitochondrial Transcription Factor ◽

Tuft Cell ◽

Mitochondrial Transcription Factor A

AbstractRORγt+ lymphocytes, including interleukin 17 (IL-17)-producing gamma delta T (γδT17) cells, T helper 17 (Th17) cells, and group 3 innate lymphoid cells (ILC3s), are important immune regulators. Compared to Th17 cells and ILC3s, γδT17 cell metabolism and its role in tissue homeostasis remains poorly understood. Here, we report that the tissue milieu shapes splenic and intestinal γδT17 cell gene signatures. Conditional deletion of mitochondrial transcription factor A (Tfam) in RORγt+ lymphocytes significantly affects systemic γδT17 cell maintenance and reduces ILC3s without affecting Th17 cells in the gut. In vivo deletion of Tfam in RORγt+ lymphocytes, especially in γδT17 cells, results in small intestine tissue remodeling and increases small intestine length by enhancing the type 2 immune responses in mice. Moreover, these mice show dysregulation of the small intestine transcriptome and metabolism with less body weight but enhanced anti-helminth immunity. IL-22, a cytokine produced by RORγt+ lymphocytes inhibits IL-13-induced tuft cell differentiation in vitro, and suppresses the tuft cell-type 2 immune circuit and small intestine lengthening in vivo, highlighting its key role in gut tissue remodeling.

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Activation of intestinal tuft cell-expressed Sucnr1 triggers type 2 immunity in the mouse small intestine

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1720758115 ◽

2018 ◽

Vol 115 (21) ◽

pp. 5552-5557 ◽

Cited By ~ 61

Author(s):

Weiwei Lei ◽

Wenwen Ren ◽

Makoto Ohmoto ◽

Joseph F. Urban ◽

Ichiro Matsumoto ◽

...

Keyword(s):

Goblet Cell ◽

Mucosal Immunity ◽

Cell Activation ◽

Nippostrongylus Brasiliensis ◽

Infectious Agents ◽

Cell Hyperplasia ◽

Type 2 Immunity ◽

Tuft Cell ◽

Tuft Cells

The hallmark features of type 2 mucosal immunity include intestinal tuft and goblet cell expansion initiated by tuft cell activation. How infectious agents that induce type 2 mucosal immunity are detected by tuft cells is unknown. Published microarray analysis suggested that succinate receptor 1 (Sucnr1) is specifically expressed in tuft cells. Thus, we hypothesized that the succinate–Sucnr1 axis may be utilized by tuft cells to detect certain infectious agents. Here we confirmed that Sucnr1 is specifically expressed in intestinal tuft cells but not in other types of intestinal epithelial cells, and demonstrated that dietary succinate induces tuft and goblet cell hyperplasia via Sucnr1 and the tuft cell-expressed chemosensory signaling elements gustducin and Trpm5. Conventional mice with a genetic Sucnr1 deficiency (Sucnr1−/−) showed diminished immune responses to treatment with polyethylene glycol and streptomycin, which are known to enhance microbiota-derived succinate, but responded normally to inoculation with the parasitic worm Nippostrongylus brasiliensis that also produces succinate. Thus, Sucnr1 is required for microbiota-induced but not for a generalized worm-induced type 2 immunity.

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Up-regulation of gasdermin C in mouse small intestine is associated with lytic cell death in enterocytes in worm-induced type 2 immunity

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2026307118 ◽

2021 ◽

Vol 118 (30) ◽

pp. e2026307118

Author(s):

Ranhui Xi ◽

Julia Montague ◽

Xiaoli Lin ◽

Chanyi Lu ◽

Weiwei Lei ◽

...

Keyword(s):

Cell Death ◽

Cell Expansion ◽

Lymphoid Cells ◽

Hek293 Cells ◽

Classical Type ◽

Wild Type ◽

Villus Atrophy ◽

Type 2 Immunity ◽

Tuft Cell

“Taste-like” tuft cells in the intestine trigger type 2 immunity in response to worm infection. The secretion of interleukin-13 (IL-13) from type 2 innate lymphoid cells (ILC2) represents a key step in the tuft cell–ILC2 cell–intestinal epithelial cell circuit that drives the clearance of worms from the gut via type 2 immune responses. Hallmark features of type 2 responses include tissue remodeling, such as tuft and goblet cell expansion, and villus atrophy, yet it remains unclear if additional molecular changes in the gut epithelium facilitate the clearance of worms from the gut. Using gut organoids, we demonstrated that IL-4 and IL-13, two type 2 cytokines with similar functions, not only induced the classical type 2 responses (e.g., tuft cell expansion) but also drastically up-regulated the expression of gasdermin C genes (Gsdmcs). Using an in vivo worm-induced type 2 immunity model, we confirmed the up-regulation of Gsdmcs in Nippostrongylus brasiliensis–infected wild-type C57BL/6 mice. Consistent with gasdermin family members being principal effectors of pyroptosis, overexpression of Gsdmc2 in human embryonic kidney 293 (HEK293) cells triggered pyroptosis and lytic cell death. Moreover, in intestinal organoids treated with IL-4 or IL-13, or in wild-type mice infected with N. brasiliensis, lytic cell death increased, which may account for villus atrophy observed in worm-infected mice. Thus, we propose that the up-regulated Gsdmc family may be major effectors for type 2 responses in the gut and that Gsdmc-mediated pyroptosis may provide a conduit for the release of antiparasitic factors from enterocytes to facilitate the clearance of worms.

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Metformin chlorination byproducts in drinking water exhibit marked toxicity to nematode worms, human cells, and mice

10.1101/2020.07.18.209890 ◽

2020 ◽

Author(s):

Runshuai Zhang ◽

Yuanzhen He ◽

Luxia Yao ◽

Jie Chen ◽

Shihao Zhu ◽

...

Keyword(s):

Type 2 Diabetes ◽

Drinking Water ◽

Small Intestine ◽

Human Cells ◽

Activated Carbon Adsorption ◽

Chlorination Process ◽

Carbon Adsorption ◽

Mouse Small Intestine ◽

Health Promoting

AbstractMetformin (MET), a worldwide used drug for type 2 diabetes, has been found with the largest amount by weight among all drugs in aquatic environment, including the drinking water sources where chlorination inevitably transforms MET into chlorination byproducts. Although MET has health-promoting properties, whether or how its chlorination byproducts affect health remains largely unknown. Here we reveal that MET chlorination byproducts Y (C4H6ClN5) and C (C4H6ClN3) exhibit marked toxicity, even higher than that of the well-known poisonous arsenic, to live worms and human cells. Moreover, both byproducts are harmful to mice and Y at 250 ng/L destroys the mouse small intestine integrity. Strikingly, we detected MET and byproduct C in worldwide drinking water. Both byproducts are increasingly produced with more MET present during chlorination process. Unprecedentedly, we unveil boiling and activated carbon adsorption as effective solutions that are in urgent demand globally for removing these byproducts from water.

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Tumor suppressor p53 regulates intestinal type 2 immunity

Nature Communications ◽

10.1038/s41467-021-23587-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Chun-Yuan Chang ◽

Jianming Wang ◽

Yuhan Zhao ◽

Juan Liu ◽

Xue Yang ◽

...

Keyword(s):

Lymphoid Cell ◽

Critical Role ◽

Intestinal Type ◽

Parasitic Infections ◽

Nippostrongylus Brasiliensis ◽

Innate Lymphoid Cell ◽

Type 2 Immunity ◽

Tuft Cell

AbstractThe role of p53 in tumor suppression has been extensively studied and well-established. However, the role of p53 in parasitic infections and the intestinal type 2 immunity is unclear. Here, we report that p53 is crucial for intestinal type 2 immunity in response to the infection of parasites, such as Tritrichomonas muris and Nippostrongylus brasiliensis. Mechanistically, p53 plays a critical role in the activation of the tuft cell-IL-25-type 2 innate lymphoid cell circuit, partly via transcriptional regulation of Lrmp in tuft cells. Lrmp modulates Ca2+ influx and IL-25 release, which are critical triggers of type 2 innate lymphoid cell response. Our results thus reveal a previously unrecognized function of p53 in regulating intestinal type 2 immunity to protect against parasitic infections, highlighting the role of p53 as a guardian of immune integrity.

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