A RIPK1-regulated inflammatory microglial state in amyotrophic lateral sclerosis.
Microglial-derived inflammation has been linked to a broad range of neurodegenerative and neuropsychiatric conditions, including amyotrophic lateral sclerosis (ALS). Using single-cell RNA sequencing, a class of Disease-Associated Microglia (DAMs) have been characterized in neurodegeneration. However, the DAM phenotype alone is insufficient to explain the functional complexity of microglia, particularly with regard to regulating inflammation that is a hallmark of many neurodegenerative diseases. Here, we identify a subclass of microglia in mouse models of ALS which we term RIPK1-Regulated Inflammatory Microglia (RRIMs). RRIMs show significant up-regulation of classical proinflammatory pathways, including increased levels of Tnf and Il1b RNA and protein. We find that RRIMs are highly regulated by TNFα signaling and that the prevalence of these microglia can be suppressed by inhibiting receptor-interacting protein kinase 1 (RIPK1) activity downstream of the TNF receptor 1. These findings help to elucidate a mechanism by which RIPK1 kinase inhibition has been shown to provide therapeutic benefit in mouse models of ALS and may provide an additional biomarker for analysis in ongoing phase 2 clinical trials of RIPK1 inhibitors in ALS.
['Mifflin|Lauren|L|0000-0003-1607-5851', 'Hu|Zhirui|Z|', 'Dufort|Connor|C|', 'Hession|Cynthia C|CC|', 'Walker|Alec J|AJ|0000-0001-7619-0662', 'Niu|Kongyan|K|', 'Zhu|Hong|H|', 'Liu|Nan|N|', 'Liu|Jun S|JS|0000-0002-4450-7239', 'Levin|Joshua Z|JZ|0000-0002-0170-3598', 'Stevens|Beth|B|', 'Yuan|Junying|J|0000-0003-2405-6036', 'Zou|Chengyu|C|0000-0002-5793-0247']
D000690:Amyotrophic Lateral Sclerosis D000818:Animals D018797:Cell Cycle Proteins D004195:Disease Models, Animal D007249:Inflammation D053583:Interleukin-1beta D026901:Membrane Transport Proteins D051379:Mice D008817:Mice, Mutant Strains D017628:Microglia D053422:Receptor-Interacting Protein Serine-Threonine Kinases D059010:Single-Cell Analysis D000072105:Superoxide Dismutase-1 D059467:Transcriptome D014409:Tumor Necrosis Factor-alpha
ALS microglia RIPK1 neuroinflammation scRNAseq