Institute for Genetics, Centre for Molecular Medicine, University of Cologne, Zülpicher Str. 47a, 50674 Cologne, Germany.
Nature. 2011 Jul 31;477(7364):330-4. doi: 10.1038/nature10273.
Intestinal immune homeostasis depends on a tightly regulated cross talk between commensal bacteria, mucosal immune cells and intestinal epithelial cells (IECs). Epithelial barrier disruption is considered to be a potential cause of inflammatory bowel disease; however, the mechanisms regulating intestinal epithelial integrity are poorly understood. Here we show that mice with IEC-specific knockout of FADD (FADD(IEC-KO)), an adaptor protein required for death-receptor-induced apoptosis, spontaneously developed epithelial cell necrosis, loss of Paneth cells, enteritis and severe erosive colitis. Genetic deficiency in RIP3, a critical regulator of programmed necrosis, 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, prevented colitis development in FADD(IEC-KO) but not in NEMO(IEC-KO) mice, 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.
肠道免疫稳态依赖于共生细菌、黏膜免疫细胞和肠上皮细胞（IECs）之间的紧密调节的串扰。上皮屏障破坏被认为是炎症性肠病的潜在原因；然而，调节肠道上皮完整性的机制尚不清楚。在这里，我们发现上皮细胞特异性敲除 FADD（FADD（IEC-KO））的小鼠，FADD 是死亡受体诱导的细胞凋亡所必需的衔接蛋白，自发发生上皮细胞坏死、潘氏细胞丢失、肠炎和严重的侵蚀性结肠炎。RIP3（程序性坏死的关键调节因子）的遗传缺陷可防止 FADD（IEC-KO）小鼠的小肠和结肠自发性病理的发生，表明肠道炎症是由 RIP3 依赖性 FADD 缺陷型 IEC 细胞坏死引发的。上皮细胞特异性抑制 CYLD，一种调节细胞坏死的去泛素化酶，可防止 FADD（IEC-KO）但不能防止 NEMO（IEC-KO）小鼠的结肠炎发生，表明这两种模型中结肠上皮细胞死亡的不同机制介导。在 FADD（IEC-KO）小鼠中，TNF 缺乏改善了结肠炎症，而 MYD88 缺乏和消除微生物群也预防了结肠炎症，表明细菌介导的 Toll 样受体信号通过诱导 TNF 和其他细胞因子的表达驱动结肠炎。然而，CYLD、TNF 或 MYD88 缺乏或消除微生物群都不能防止 FADD（IEC-KO）小鼠的潘氏细胞丢失和肠炎，表明不同的机制驱动 FADD 缺陷型 IECs 在小肠和大肠中发生 RIP3 依赖性坏死。因此，通过抑制 RIP3 介导的 IEC 坏死，FADD 可保持上皮屏障完整性和抗菌防御，维持内稳态并预防慢性肠道炎症。总之，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内稳态至关重要，并表明 IEC 细胞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有助于肠道炎症。
