Receptor interacting protein kinase 1 (RIPK1) is a cytosolic multidomain protein that controls cell life and death. While RIPK1 promotes cell death through its kinase activity, it also functions as a scaffold protein to promote cell survival by inhibiting FADD-caspase 8-dependent apoptosis and RIPK3-MLKL-dependent necroptosis. This pro-survival function is highlighted by excess cell death and perinatal lethality in Ripk1^−/− mice. Recently, loss of function mutation of RIPK1 was found in patients with immunodeficiency and inflammatory bowel diseases. Hematopoietic stem cell transplantation restored not only immunodeficiency but also intestinal inflammatory pathology, indicating that RIPK1 in hematopoietic cells is critical to maintain intestinal immune homeostasis. Here, we generated dendritic cell (DC)-specific Ripk1^−/− mice in a genetic background with loss of RIPK1 kinase activity and found that the mice developed spontaneous colonic inflammation characterized by increased neutrophil and Ly6C⁺ monocytes. In addition, these mice were highly resistant to injury-induced colitis. The increased colonic inflammation and the resistance to colitis were restored by dual inactivation of RIPK3 and FADD, but not by inhibition of RIPK3, MLKL, or ZBP1 alone. Altogether, these results reveal a scaffold activity-dependent role of RIPK1 in DC-mediated maintenance of colonic immune homeostasis.

受体相互作用蛋白激酶 1 (RIPK1) 是一种控制细胞生死的胞质多结构域蛋白。虽然 RIPK1 通过其激酶活性促进细胞死亡，但它也作为支架蛋白发挥作用，通过抑制 FADD-半胱天冬酶 8 依赖性细胞凋亡和 RIPK3-MLKL 依赖性坏死性凋亡来促进细胞存活。Ripk1 ^-/-小鼠的过度细胞死亡和围产期致死率突出了这种促生存功能。最近，RIPK1的功能缺失突变在患有免疫缺陷和炎症性肠病的患者中发现。造血干细胞移植不仅可以恢复免疫缺陷，还可以恢复肠道炎症病理，表明造血细胞中的 RIPK1 对维持肠道免疫稳态至关重要。在这里，我们在 RIPK1 激酶活性丧失的遗传背景中生成了树突状细胞 (DC) 特异性Ripk1 ^−/−小鼠，并发现小鼠出现了以中性粒细胞和 Ly6C ^{+增加为特征的自发性结肠炎症}单核细胞。此外，这些小鼠对损伤引起的结肠炎具有高度抵抗力。增加的结肠炎症和对结肠炎的抵抗力通过 RIPK3 和 FADD 的双重失活得到恢复，但不是通过单独抑制 RIPK3、MLKL 或 ZBP1 来恢复。总之，这些结果揭示了 RIPK1 在 DC 介导的结肠免疫稳态维持中的支架活性依赖性作用。