中国科学院上海有机化学研究所袁钧瑛课题组的一项最新研究探明了INPP5D抑制RIPK1激酶可抑制多种促炎介质和晚发性阿尔茨海默病危险因素的表达。相关论文于2026年2月2日发表在《免疫学》杂志上。

该课题组研究人员发现，一个重要的LOAD风险基因INPP5D的N端SH2结构域在p-Y383位点直接与细胞死亡调控因子RIPK1相互作用，抑制RIPK1激酶的激活。小胶质细胞INPP5D缺乏细胞自主促进RIPK1介导的多种LOAD风险基因、促炎细胞因子、补体和ROS介质以及促炎信号介质，如Toll样受体（TLRs）、MyD88、Nlrp3、gasdermin D和Zbp1的转录诱导。在与人类阿尔茨海默病（AD）发病机制相关的小胶质亚型中发现了RIPK1调控的小胶质转录组特征。

此外，小胶质细胞INPP5D缺乏以非细胞自主的方式促进了衰老依赖性RIPK1介导的神经元TDP-43病理、神经元损失和运动功能障碍的发展。他们的数据表明，INPP5D作为细胞内变阻器调节RIPK1介导的神经炎症，促进衰老相关的神经退行性疾病，包括LOAD和AD-肌萎缩性侧索硬化症合并症。

据介绍，全基因组关联研究强烈暗示迟发性阿尔茨海默病（LOAD）的神经炎症。小胶质细胞中表达的基因丰富了LOAD的遗传风险位点，但小胶质细胞LOAD风险基因之间的关系尚不清楚。

附：英文原文

Title: Repression of RIPK1 kinase by INPP5D inhibits expression of diverse proinflammatory mediators and late-onset Alzheimer’s disease risk factors

Author: Xingxing Xie, Jianping Liu, Wei Liang, Yici Zhang, Xueqi Gong, Shenghao Yuan, Chunting Qi, Maoqing Huang, Linyu Shi, Meiling Hou, Mengmeng Zhang, Wei Liu, Weimin Sun, Yaqi Wu, Cui Li, Ze Cao, Hongyang Jing, Lihui Qian, Jingli Liu, Shufen Yuan, Qiong Wang, Yong Shen, Zhijun Liu, Yunxia Li, Heling Pan, Bing Zhu, Bing Shan, Kaiwen He, Wenyuan Wang, Chengyu Zou, Ying Li, James J. Chou, Junying Yuan

Issue&Volume: 2026-02-02

Abstract: Genome-wide association studies strongly implicate neuroinflammation in late-onset Alzheimer’s disease (LOAD). Genetic risk loci for LOAD are enriched for genes expressed in microglia, but the relationship among microglial LOAD risk genes has been unclear. We found that the N-terminal SH2 domain of INPP5D, an important LOAD risk gene, directly interacted with the cell death regulator RIPK1 at p-Y383 to suppress RIPK1 kinase activation. Microglial INPP5D deficiency cell-autonomously promoted RIPK1-mediated transcriptional induction of diverse LOAD risk genes, proinflammatory cytokines, complements, and ROS mediators, as well as proinflammatory signaling mediators such as Toll-like receptors (TLRs), MyD88, Nlrp3, gasdermin D, and Zbp1. RIPK1-regulated microglial transcriptomic signatures were found in microglial subtypes implicated in human Alzheimer’s disease (AD) pathogenesis. Furthermore, microglial INPP5D deficiency promoted aging-dependent RIPK1-mediated development of neuronal TDP-43 pathology, neuronal loss, and motor dysfunction in a non-cell-autonomous manner. Our data suggest that INPP5D functions as an intracellular rheostat in regulating RIPK1-mediated neuroinflammation for promoting aging-related neurodegenerative diseases, including LOAD and AD-amyotrophic lateral sclerosis comorbidity.

DOI: 10.1016/j.immuni.2026.01.014

Source: https://www.cell.com/immunity/abstract/S1074-7613(26)00036-1