FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation
FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation
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DOI：
10.1038/nature10273
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发表时间：
2011-09-15
期刊：
影响因子：
64.8
通讯作者：
Pasparakis, Manolis
中科院分区：
文献类型：
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作者：
Welz, Patrick-Simon;Wullaert, Andy;Pasparakis, Manolis
肠道免疫稳态取决于共生细菌、粘膜免疫细胞和肠上皮细胞 (IEC) 之间严格调节的相互作用(1-4)。上皮屏障破坏被认为是炎症性肠病的潜在原因；然而，人们对调节肠上皮完整性的机制知之甚少(1,5)。在这里，我们发现 IEC 特异性敲除 FADD (FADD(IEC-KO))（一种死亡受体诱导细胞凋亡所需的衔接蛋白 (6)）的小鼠会自发出现上皮细胞坏死、潘氏细胞丢失、肠炎和严重糜烂性结肠炎。 RIP3 是程序性坏死的关键调节因子 (7-9)，其遗传缺陷阻止了 FADD (IEC-KO) 小鼠小肠和结肠自发病理的发展，表明肠道炎症是由 FADD 缺陷 IEC 的 RIP3 依赖性死亡引发的。 CYLD 是一种调节细胞坏死的去泛素酶 (10)，上皮特异性抑制可阻止 FADD (IEC-KO) 中结肠炎的发展，但不能阻止 NEMOIEC-KO 小鼠 (11)，这表明在这两种模型中介导结肠上皮细胞死亡的机制不同。在 FADD（IEC-KO）小鼠中，TNF 缺乏可改善结肠炎症，而 MYD88 缺乏以及微生物群的消除则可预防结肠炎症，这表明细菌介导的 Toll 样受体信号传导通过诱导 TNF 和其他细胞因子的表达来驱动结肠炎。然而，CYLD、TNF 或 MYD88 缺陷或微生物群的消除都不能阻止 FADD (IEC-KO) 小鼠的潘氏细胞丢失和肠炎，这表明不同的机制驱动小肠和大肠中 FADD 缺陷 IEC 的 RIP3 依赖性坏死。因此，通过抑制 RIP3 介导的 IEC 坏死，FADD 可以保持上皮屏障完整性和抗菌防御，维持体内平衡并预防慢性肠道炎症。总的来说，这些结果表明，防止 RIP3 介导的上皮细胞死亡的机制对于维持肠道稳态至关重要，并表明 IEC 的程序性坏死可能与炎症性肠病的发病机制有关，其中潘氏细胞和屏障缺陷被认为是导致肠道炎症的原因。
Intestinal immune homeostasis depends on a tightly regulated cross talk between commensal bacteria, mucosal immune cells and intestinal epithelial cells (IECs)(1-4). Epithelial barrier disruption is considered to be a potential cause of inflammatory bowel disease; however, the mechanisms regulating intestinal epithelial integrity are poorly understood(1,5). Here we show that mice with IEC-specific knockout of FADD (FADD(IEC-KO)), an adaptor protein required for death-receptor-induced apoptosis(6), spontaneously developed epithelial cell necrosis, loss of Paneth cells, enteritis and severe erosive colitis. Genetic deficiency in RIP3, a critical regulator of programmed necrosis(7-9), prevented the development of spontaneous pathology in both the small intestine and colon of FADD(IEC-KO) mice, demonstrating that intestinal inflammation is triggered by RIP3-dependent death of FADD-deficient IECs. Epithelial-specific inhibition of CYLD, a deubiquitinase that regulates cellular necrosis(10), prevented colitis development in FADD(IEC-KO) but not in NEMOIEC-KO mice(11), showing that different mechanisms mediated death of colonic epithelial cells in these two models. In FADD(IEC-KO) mice, TNF deficiency ameliorated colon inflammation, whereas MYD88 deficiency and also elimination of the microbiota prevented colon inflammation, indicating that bacteria-mediated Toll-like-receptor signalling drives colitis by inducing the expression of TNF and other cytokines. However, neither CYLD, TNF or MYD88 deficiency nor elimination of the microbiota could prevent Paneth cell loss and enteritis in FADD(IEC-KO) mice, showing that different mechanisms drive RIP3-dependent necrosis of FADD-deficient IECs in the small and large bowel. Therefore, by inhibiting RIP3-mediated IEC necrosis, FADD preserves epithelial barrier integrity and antibacterial defence, maintains homeostasis and prevents chronic intestinal inflammation. Collectively, these results show that mechanisms preventing RIP3-mediated epithelial cell death are critical for the maintenance of intestinal homeostasis and indicate that programmed necrosis of IECs might be implicated in the pathogenesis of inflammatory bowel disease, in which Paneth cell and barrier defects are thought to contribute to intestinal inflammation.