Sprouty2 limits intestinal tuft and goblet cell numbers through GSK3β-mediated restriction of epithelial IL-33.
Sprouty2 limits intestinal tuft and goblet cell numbers through GSK3β-mediated restriction of epithelial IL-33.
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Sprouty 2通过GSK 3 β介导的上皮IL-33的限制来限制肠簇和杯状细胞的数量。
DOI：
10.1038/s41467-021-21113-7
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发表时间：
2021-02-05
影响因子：
16.6
通讯作者：
Frey MR
中科院分区：
文献类型：
--
作者：
Schumacher MA;Hsieh JJ;Liu CY;Appel KL;Waddell A;Almohazey D;Katada K;Bernard JK;Bucar EB;Gadeock S;Maselli KM;Washington MK;Grikscheit TC;Warburton D;Rosen MJ;Frey MR
肠道细胞分化的动态调节对于体内平衡和对损伤或炎症的反应都是至关重要的。Sprouty2是一种细胞内信号调节因子，控制着包括PI3K和MAPK在内的与分化有关的通路，这些通路在炎症性肠病中调节失调。在这里，我们问Sprouty2是否控制分泌细胞分化和对结肠炎的反应。我们报告说，结肠上皮芽组织缺失会导致簇状和杯状细胞群的扩大。Sprouty2缺失诱导PI3K/Akt信号转导，导致GSK3β抑制和上皮细胞白介素33表达。在体内，这会导致间质IL-13+细胞增加。IL-13在体外和体内都能诱导杯状细胞和杯状细胞的增殖。Sprouty2被急性炎症下调；这似乎是一种保护性反应，如VillinCre；Sprouty2F/F小鼠对DSS结肠炎具有抵抗力。相反，Sprouty2在慢性结肠炎和炎症性肠病患者的结肠中升高，表明这种保护性的上皮-间质信号机制在疾病中丢失。结肠分泌细胞数量的动态调节是肠道损伤和炎症反应的重要组成部分。在这里，作者表明，肠上皮细胞内信号调节因子Sprouty2的丢失是对损伤的保护性反应，导致分泌细胞数量增加，从而限制结肠炎的严重程度。
Dynamic regulation of intestinal cell differentiation is crucial for both homeostasis and the response to injury or inflammation. Sprouty2, an intracellular signaling regulator, controls pathways including PI3K and MAPKs that are implicated in differentiation and are dysregulated in inflammatory bowel disease. Here, we ask whether Sprouty2 controls secretory cell differentiation and the response to colitis. We report that colonic epithelial Sprouty2 deletion leads to expanded tuft and goblet cell populations. Sprouty2 loss induces PI3K/Akt signaling, leading to GSK3β inhibition and epithelial interleukin (IL)-33 expression. In vivo, this results in increased stromal IL-13+ cells. IL-13 in turn induces tuft and goblet cell expansion in vitro and in vivo. Sprouty2 is downregulated by acute inflammation; this appears to be a protective response, as VillinCre;Sprouty2F/F mice are resistant to DSS colitis. In contrast, Sprouty2 is elevated in chronic colitis and in colons of inflammatory bowel disease patients, suggesting that this protective epithelial-stromal signaling mechanism is lost in disease. Dynamic regulation of colonic secretory cell numbers is a critical component of the response to intestinal injury and inflammation. Here, the authors show that loss of the intracellular signalling regulator Sprouty2 in the intestinal epithelial cells is a protective response to injury that leads to increased secretory cell numbers, thus limiting colitis severity.
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影响因子：
12.4
作者：
Almohazey, Dana;Lo, Yuan-Hung;Frey, Mark R.
通讯作者：
Frey, Mark R.
影响因子：
64.8
作者：
Gerbe F;Sidot E;Smyth DJ;Ohmoto M;Matsumoto I;Dardalhon V;Cesses P;Garnier L;Pouzolles M;Brulin B;Bruschi M;Harcus Y;Zimmermann VS;Taylor N;Maizels RM;Jay P
通讯作者：
Jay P
影响因子：
2.6
作者：
de Maximy, AA;Nakatake, Y;Bellusci, S
通讯作者：
Bellusci, S
影响因子：
5.4
作者：
Elliott, DE;Setiawan, T;Weinstock, JV
通讯作者：
Weinstock, JV
影响因子：
5.7
作者：
Feng, Yin-Hsun;Tsao, Chao-Jung;Lee, Jeng-Chang
通讯作者：
Lee, Jeng-Chang