RIPK1 activation mediates neuroinflammation and disease progression in multiple sclerosis.

Matija Zelic,Michael Lamorte,Amy Mahan,Aislinn Keane,Fabrizio Pontarelli,Cheng Zhu,Pequita Loring,Lilu Guo,Lisa Woodworth,Ross Gruber,Tai-He Xia,Dimitry Ofengeim,Yi Ren,Egil Lien,Timothy Hammond,Boyao Zhang,Alexei Degterev,Pontus Orning

doi:10.1016/j.celrep.2021.109112

Abstract

SUMMARYReceptor interacting protein kinase 1 (RIPK1) mediates cell death and inflammatory signaling and is increased in multiple sclerosis (MS) brain samples. Here, we investigate the role of glial RIPK1 kinase activity in mediating MS pathogenesis. We demonstrate RIPK1 levels correlate with MS disease progression. We find microglia are susceptible to RIPK1-mediated cell death and identify an inflammatory gene signature that may contribute to the neuroinflammatory milieu in MS patients. We uncover a distinct role for RIPK1 in astrocytes in regulating inflammatory signaling in the absence of cell death and confirm RIPK1-kinase-dependent regulation in human glia. Using a murine MS model, we show RIPK1 inhibition attenuates disease progression and suppresses deleterious signaling in astrocytes and microglia. Our results suggest RIPK1 kinase activation in microglia and astrocytes induces a detrimental neuroinflammatory program that contributes to the neurodegenerative environment in progressive MS.

Highlights

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by neuroinflammation, demyelination, and axonal degeneration
Receptor interacting protein kinase 1 (RIPK1) signaling is upregulated in progressive MS To explore the role of RIPK1 in MS, we examined RIPK1 expression in post-mortem brain samples from patient-derived white matter lesions and normal-appearing white matter (NAWM) in control subjects
RIPK1 reactivity was increased in the Tris-buffered saline (TBS)/Triton-soluble fraction in MS brain samples compared with NAWM controls, RIPK1 expression was significantly elevated in the insoluble fraction of primary progressive MS (PPMS) samples (Figures 1A and 1B)

Summary

Introduction

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by neuroinflammation, demyelination, and axonal degeneration. Most patients are initially diagnosed with relapsing/remitting MS (RRMS), many patients have worsening symptoms over time and gradual progression to secondary progressive MS (SPMS) (Inojosa et al, 2021). The time courses of SPMS and PPMS are markedly different, the underlying pathologies are similar (Lassmann, 2019). Current therapies are efficacious in treating symptoms associated with RRMS, but therapeutic options for progressive disease remain limited (Ciotti and Cross, 2018; Lassmann, 2017). A key aspect thought to regulate MS progression is the mechanism by which the CNS responds to peripheral immune infiltration. Microglia are the most abundant immune cells in active MS lesions (Kuhlmann et al, 2017); their altered function and ability to interact with other CNS-resident cells, like astrocytes, is a critical determinant of the CNS milieu in disease. Astrocytes can contribute to pathology in MS and other neurodegenerative diseases (Liddelow et al, 2017; Ponath et al, 2018a; Wheeler and Quintana, 2019), but the interplay of these two cell types in the context of MS has not been fully explored

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