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

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 p...

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Autores principales: Linzey, Michael, DiSano, Krista, Welsh, Nora, Pachner, Andrew, Gilli, Francesca
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9360327/
https://www.ncbi.nlm.nih.gov/pubmed/35958570
http://dx.doi.org/10.3389/fimmu.2022.924734
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author Linzey, Michael
DiSano, Krista
Welsh, Nora
Pachner, Andrew
Gilli, Francesca
author_facet Linzey, Michael
DiSano, Krista
Welsh, Nora
Pachner, Andrew
Gilli, Francesca
author_sort Linzey, Michael
collection PubMed
description 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.
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spelling pubmed-93603272022-08-10 Divergent complement system activation in two clinically distinct murine models of multiple sclerosis Linzey, Michael DiSano, Krista Welsh, Nora Pachner, Andrew Gilli, Francesca Front Immunol Immunology 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. Frontiers Media S.A. 2022-07-26 /pmc/articles/PMC9360327/ /pubmed/35958570 http://dx.doi.org/10.3389/fimmu.2022.924734 Text en Copyright © 2022 Linzey, DiSano, Welsh, Pachner and Gilli https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Linzey, Michael
DiSano, Krista
Welsh, Nora
Pachner, Andrew
Gilli, Francesca
Divergent complement system activation in two clinically distinct murine models of multiple sclerosis
title Divergent complement system activation in two clinically distinct murine models of multiple sclerosis
title_full Divergent complement system activation in two clinically distinct murine models of multiple sclerosis
title_fullStr Divergent complement system activation in two clinically distinct murine models of multiple sclerosis
title_full_unstemmed Divergent complement system activation in two clinically distinct murine models of multiple sclerosis
title_short Divergent complement system activation in two clinically distinct murine models of multiple sclerosis
title_sort divergent complement system activation in two clinically distinct murine models of multiple sclerosis
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9360327/
https://www.ncbi.nlm.nih.gov/pubmed/35958570
http://dx.doi.org/10.3389/fimmu.2022.924734
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