2. Academic Validation
  3. Repression of RIPK1 kinase by INPP5D inhibits expression of diverse proinflammatory mediators and late-onset Alzheimer's disease risk factors

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

  • Immunity. 2026 Feb 10;59(2):419-437.e11. doi: 10.1016/j.immuni.2026.01.014.
Xingxing Xie 1,  Jianping Liu 2,  Wei Liang 1,  Yici Zhang 1,  Xueqi Gong 3,  Shenghao Yuan 4,  Chunting Qi 2,  Maoqing Huang 1,  Linyu Shi 2,  Meiling Hou 5,  Mengmeng Zhang 2,  Wei Liu 6,  Weimin Sun 1,  Yaqi Wu 2,  Cui Li 7,  Ze Cao 2,  Hongyang Jing 2,  Lihui Qian 2,  Jingli Liu 2,  Shufen Yuan 8,  Qiong Wang 8,  Yong Shen 8,  Zhijun Liu 9,  Yunxia Li 10,  Heling Pan 2,  Bing Zhu 7,  Bing Shan 2,  Kaiwen He 2,  Wenyuan Wang 2,  Chengyu Zou 2,  Ying Li 2,  James J Chou 11,  Junying Yuan 12
Affiliations

Affiliations

  • 1 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; Shanghai Key Laboratory of Aging Studies, Shanghai 201203, China.
  • 2 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201203, China; Shanghai Key Laboratory of Aging Studies, Shanghai 201203, China.
  • 3 School of Life Sciences, Fudan University, Shanghai 200438, China.
  • 4 School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 5 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201203, China; Nankai University, Tianjin, China; Shanghai Key Laboratory of Aging Studies, Shanghai 201203, China.
  • 6 Lingang Laboratory, Shanghai 200031, China.
  • 7 Center for Translational Neurodegeneration and Regenerative Therapy, Tongji Hospital affiliated to Tongji University, Shanghai 200092, China.
  • 8 Department of Neurology, Institute on Aging and Brain Disorders, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
  • 9 National Facility for Protein Science, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201203, China.
  • 10 Department of Neurology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China; Department of Neurology, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
  • 11 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201203, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201203, China.
  • 12 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201203, China; Shanghai Key Laboratory of Aging Studies, Shanghai 201203, China. Electronic address: [email protected].
PMID: 41633359 DOI: 10.1016/j.immuni.2026.01.014
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.

Keywords

ALS; INPP5D; LOAD; RIPK1; TDP-43 pathology; aging; amyotrophic lateral sclerosis; late-onset Alzheimer's disease; microglia; neuroinflammation; neuronal loss; pro-inflammatory mediators.

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