Necroptosis of intestinal epithelial cells induces type 3 innate lymphoid cell-dependent lethal ileitis.
Necroptosis of intestinal epithelial cells induces type 3 innate lymphoid cell-dependent lethal ileitis.
复制标题
肠上皮细胞坏死性凋亡诱导 3 型先天性淋巴细胞依赖性致死性回肠炎。
DOI：
10.1016/j.isci.2019.05.011
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发表时间：
2019
期刊：
影响因子：
5.8
通讯作者：
Nakano H.
中科院分区：
文献类型：
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作者：
Shindo R;Ohmuraya M;Komazawa-Sakon S;Miyake S;Deguchi Y;Yamazaki S;Nishina T;Yoshimoto T;Kakuta S;Koike M;Uchiyama Y;Konishi H;Kiyama H;Mikami T;Moriwaki K;Araki K;Nakano H.
CFLARs编码的一种短形式的细胞FLICE抑制蛋白促进坏死性凋亡。虽然坏死性凋亡涉及各种病理条件，但详细机制尚未完全了解。在这里，我们产生了将CFLARs整合到X染色体上的转基因小鼠。所有雄性CFLARs Tg小鼠均因重度回肠炎在围产期死亡。虽然在CFLARs Tg小鼠的各种组织中观察到坏死性凋亡，但大量肠上皮细胞（IEC）因凋亡而死亡。Ripk 3或Mlkl（坏死性凋亡的必需基因）的缺失防止了坏死性凋亡和凋亡，并挽救了CFLARs Tg小鼠的死亡率。在CFLARs Tg小鼠中，3型先天性淋巴样细胞（ILC 3）被激活并随着白细胞介素-22（IL-22）的上调而沿着募集到小肠。ILC 3或IL 22的缺失通过防止细胞凋亡而不是IEC的坏死性凋亡来挽救CFLARs Tg小鼠的致死率。总之，ILC 3的坏死性凋亡依赖性激活以IL-22依赖性方式诱导致死性回肠炎。
A short form of cellular FLICE-inhibitory protein encoded byCFLARspromotes necroptosis. Although necroptosis is involved in various pathological conditions, the detailed mechanisms are not fully understood. Here we generated transgenic mice whereinCFLARswas integrated onto the X chromosome. All maleCFLARsTg mice died perinatally due to severe ileitis. Although necroptosis was observed in various tissues ofCFLARsTg mice, large numbers of intestinal epithelial cells (IECs) died by apoptosis. Deletion ofRipk3orMlkl, essential genes of necroptosis, prevented both necroptosis and apoptosis, and rescued lethality ofCFLARsTg mice. Type 3 innate lymphoid cells (ILC3s) were activated and recruited to the small intestine along with upregulation ofinterleukin-22(Il22) inCFLARsTg mice. Deletion of ILC3s orIl22rescued lethality ofCFLARsTg mice by preventing apoptosis, but not necroptosis of IECs. Together, necroptosis-dependent activation of ILC3s induces lethal ileitis in an IL-22-dependent manner.