Homeostatic regulation of RIPK1 activation by INPP5D controls the microglial transcription of LOAD risk factors and diverse proinflammatory mediators (PRJCA049268)
Genome-wide Association Studies strongly implicate the roles of neuroinflammation in LOAD. RIPK1 is an important mediator of neuroinflammation. Here we investigate the interaction of INPP5D, an important LOAD risk gene, with RIPK1. We show that the N-terminal SH2 domain of INPP5D directly interacts with RIPK1 to suppress its kinase activation. We show that microglial INPP5D deficiency promotes RIPK1-mediated transcriptional induction of diverse LOAD risk genes, proinflammatory cytokines, complement factors and regulators of ROS, as well as key proinflammatory mediators including TLRs, inflammasomes and interferons. RIPK1-mediated microglial transcriptomic signatures are found in the key microglial subtypes implicated in the pathogenesis of human AD. Microglial INPP5D deficiency in mice promotes aging-dependent RIPK1-mediated development of dystrophic microglia, loss of motor neurons and motor dysfunction. Our data suggest that INPP5D functions as a key intracellular rheostat in regulating RIPK1-mediated neuroinflammation for aging-related onset of LOAD and other neurodegenerative diseases.