A RIPK1-regulated inflammatory microglial state in amyotrophic lateral sclerosis

Abstract

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.

Immune Signaling Kinases in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD)

“…Even though there is no causal evidence linking RIPK1 mutations to ALS, this gene was shown to mediate axonal degeneration by promoting inflammation and subsequent oligodendrocytes necroptosis in ALS [33], and a proinflammatory role of RIPK1 kinase activity in the CNS in association with TBK1 was demonstrated, as mentioned above [27]. Importantly, a recent study based on single-cell RNA sequencing has identified a RIPK1-regulated inflammatory microglial (RRIM) subset in early-stage SOD1 G93A mice [34]. Differently from Disease-Associated Microglia (DAM), the RRIM state was characterized by up-regulation of classic proinflammatory pathways, and was found to peak at an earlier time point in the ALS model, compared to the DAM phenotype [34].…”

The GM2 gangliosidoses: Unlocking the mysteries of pathogenesis and treatment

“…Models of other lower motor neuron (LMN) degeneration including Sod1 and Optn deficient mouse models of ALS demonstrate the interplay between microglia and oligodendrocytes influencing LMN cell survival at the spinal cord level [ 103 ]. Microglial proliferation, cytokine release, and activation of receptors such as RIPK1 are a critical component of cell death in neurodegeneration [ 103 – 105 ].…”

“…Models of other lower motor neuron (LMN) degeneration including Sod1 and Optn deficient mouse models of ALS demonstrate the interplay between microglia and oligodendrocytes influencing LMN cell survival at the spinal cord level [ 103 ]. Microglial proliferation, cytokine release, and activation of receptors such as RIPK1 are a critical component of cell death in neurodegeneration [ 103 – 105 ]. “Cross-talk” between activated microglia and oligodendrocytes results in subclasses of microglia that are directly involved in neurodegeneration, loss of myelin coverings and subsequent retrograde degeneration of anterior horn cells [ 104 ].…”

Genetic inhibition of RIPK3 ameliorates functional outcome in controlled cortical impact independent of necroptosis

“…Another is cleavage of RIPK1 by caspase-8. Both mechanisms could serve as potential regulatory mechanisms to promote survival of microglia and macrophages, or to direct inflammatory signaling away from a neurodegenerative RIPK1-dependent pro-inflammatory phenotype such as that observed in a subclass of microglia in ALS models [ 68 ]. These speculations deserve further investigation in CCI models.…”