A RIPK1-regulated inflammatory microglial state in amyotrophic lateral sclerosis

Abstract

Significance Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. Inhibition of RIPK1, a kinase which regulates cell death and neuroinflammation, has been efficacious in treating mouse models of ALS. RIPK1 inhibitors have reached phase 2 clinical trials in ALS patients. Here, we explore the impact of RIPK1 inhibition on microglial-mediated neuroinflammation in ALS mouse models. We find that there is a subclass of microglia which produces proinflammatory cytokines in a RIPK1-dependent manner, and that this population is reduced by RIPK1 inhibition. We believe that these inflammatory microglia are a hallmark of ALS which may be clinically relevant in advancing RIPK1 inhibitors as a potential ALS therapy.