Divergent complement system activation in two clinically distinct murine models of multiple sclerosis

Abstract

Multiple sclerosis (MS) is a neurological disease featuring neuroinflammation and neurodegeneration in young adults. So far, most research has focused on the peripheral immune system, which appears to be the driver of acute relapses. Concurrently, the mechanisms underlying neurodegeneration in the progressive forms of the disease remain unclear. The complement system, a molecular component of the innate immunity, has been recently implicated in several neurological disorders, including MS. However, it is still unknown if the complement proteins detected in the central nervous system (CNS) are actively involved in perpetuating chronic inflammation and neurodegeneration. To address this knowledge gap, we compared two clinically distinct mouse models of MS: 1) proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (rEAE) resembling a relapsing-remitting disease course, and 2) Theiler’s murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) resembling a progressive disease. Real-time PCR was performed in the spinal cord of rEAE mice, TMEV-IDD mice and age-matched sham controls to quantify gene expression for a broad range of complement components. In both experimental models, we found significantly increased expression of complement factors, such as C1q, C3, CfB, and C3aR. We showed that the complement system, specifically the classical complement pathway, was associated with TMEV-IDD pathogenesis, as the expression of C1q, C3 and C3aR1 were all significantly correlated to a worse disease outcome (all P≤0.0168). In line with this finding, C1q and C3 deposition was observed in the spinal cord of TMEV-IDD mice. Furthermore, C1q deposition was detected in spinal cord regions characterized by inflammation, demyelination, and axonal damage. Conversely, activation of the classical complement cascade seemed to result in protection from rEAE (C1q: P=0.0307). Interestingly, the alternative pathway related to a worse disease outcome in rEAE (CFb: P=0.0006). Overall, these results indicate potential divergent roles for the complement system in MS. The chronic-progressive disease form is more reliant on the activation of the classic complement pathway, while protecting from acute relapses. Conversely, relapsing MS appears more likely affected by the alternative pathway. Understanding the functions of the complement system in MS is critical and can lead to better, more targeted therapies in the future.

The validity of animal models to explore the pathogenic role of the complement system in multiple sclerosis: A review

“…In this context, the viral infection animal models of MS, such as the TMEV and MHV-induced demyelination models, serve as a perfect template to explore the role of viruses in the pathogenesis of this condition and the importance of complement system activation ( Friedmann and Lorch, 1985 ; Katz-Levy et al, 1999 ; Mecha et al, 2013 ; Gilli et al, 2016a , b ). In line with this, using the TMEV model, Linzey et al (2022) found an increased expression of both classical and alternative complement pathway components. However, only the classical complement pathway activation as assessed by the level of C1q, C3, and C3aR1 expression, correlated with worse disease outcomes.…”

Theiler’s virus-induced demyelinating disease as an infectious model of progressive multiple sclerosis

“…In TMEV-IDD, activation of the CS is evident at the early and chronic stages of the disease ( Libbey et al, 2010 ; DiSano et al, 2019a ; Linzey et al, 2022 ). In a recent study, the CS, specifically the classical complement pathway, was associated with TMEV-IDD pathogenesis, as the expression of critical complement components like C1q, C3, and C3aR1 were all correlated to a worse disease outcome ( Linzey et al, 2022 ).…”

“…In TMEV-IDD, activation of the CS is evident at the early and chronic stages of the disease ( Libbey et al, 2010 ; DiSano et al, 2019a ; Linzey et al, 2022 ). In a recent study, the CS, specifically the classical complement pathway, was associated with TMEV-IDD pathogenesis, as the expression of critical complement components like C1q, C3, and C3aR1 were all correlated to a worse disease outcome ( Linzey et al, 2022 ). In line with this finding, C1q and C3 depositions were observed in CNS regions characterized by inflammation, i.e., microglia and astrocytes activation, demyelination, and axonal damage ( Linzey et al, 2022 ).…”

“…In a recent study, the CS, specifically the classical complement pathway, was associated with TMEV-IDD pathogenesis, as the expression of critical complement components like C1q, C3, and C3aR1 were all correlated to a worse disease outcome ( Linzey et al, 2022 ). In line with this finding, C1q and C3 depositions were observed in CNS regions characterized by inflammation, i.e., microglia and astrocytes activation, demyelination, and axonal damage ( Linzey et al, 2022 ). These results reveal an association between TMEV-IDD and activation of the classical complement pathway by antigen-antibody immune complexes that appear to contribute significantly to the disease severity.…”

“…Also, reactive astrocytes have been shown to release, in the CNS, the C3 factor, i.e., the central protein in the CS ( Pekna and Pekny, 2021 ). Accordingly, throughout TMEV-IDD, a significant upregulation of C3 expression and deposition is observed as stimulated by reactive astrocytes ( DiSano et al, 2019a ; Linzey et al, 2022 ).…”