An “Outside-In” and “Inside-Out” Consideration of Complement in the Multiple Sclerosis Brain: Lessons From Development and Neurodegenerative Diseases

Morgan, B. Paul; Gommerman, Jennifer L.; Ramaglia, Valeria

doi:10.3389/fncel.2020.600656

Cited by 36 publications

(33 citation statements)

References 236 publications

(362 reference statements)

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“…There has been a recent surge of interest in describing the effects of the complement system in neurodevelopmental and neurological disorders (9,42). These studies indicate that the complement system likely plays a role in the pathogenesis of MS (43). However, the extent and nature of complement activation and its contribution to disease phenotype remain unclear.…”

Section: Discussionmentioning

confidence: 99%

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

Linzey

DiSano²,

Welsh³

et al. 2022

Front. Immunol.

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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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Section: Discussionmentioning

confidence: 99%

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

Linzey

DiSano²,

Welsh³

et al. 2022

Front. Immunol.

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“…However, two different mechanisms, the “outside-in” theory and the “inside-out” paradigm, have been proposed. The first one refers to the recognition of several antigens by antibodies, as well as antibody-independent myelin tagging, as the starting point for initiating the immune response, while the second one postulates that damaged myelin could act as a potent trigger for the complement system (reviewed in 88 ). In animal models and MS patients, complement component deposition around the demyelinating plaques has been described, 89–92 as well as an increase in C4a levels in plasma 93 and C3, C4b and the MAC in the CSF of patients.…”

Section: Complement In the Brainmentioning

confidence: 99%

The Role of Complement in Synaptic Pruning and Neurodegeneration

Gómez-Arboledas

Acharya

Tenner

2021

ITT

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The complement system, an essential part of the innate immune system, is composed of a group of secreted and membrane proteins that collectively participate in maintaining the function of the healthy and diseased brain. However, an inappropriate activation of the complement system has been related to an inflammatory response in multiple diseases, such as stroke, traumatic brain injury, multiple sclerosis, and Alzheimer’s disease, as well as Zika infection and radiotherapy. In addition, C1q and C3 (initial activation components of the complement cascade) have been shown to play a key beneficial role in the refinement of synaptic circuits during developmental stages and adult plasticity. Nevertheless, excessive synaptic pruning in the adult brain can be detrimental and has been associated with synaptic loss in several pathological conditions. In this brief review, we will discuss the role of the complement system in synaptic pruning as well as its contribution to neurodegeneration and cognitive deficits. We also mention potential therapeutic approaches to target the complement system to treat several neuroinflammatory diseases and unintended consequences of radiotherapy.

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“…The immune and inflammatory responses in the MS brain are complex and involve peripheral cell infiltration, BBB disruption, resident glial cell activation working together. Evidence pointing to the possibility of increased complement factors being involved in pathogenesis of MS continue to emerge [ 126 , 127 , 128 , 129 , 130 ]. Therefore, only the role of complement components in demyelination and neurodegenerative symptoms in this section will be discussed.…”

Section: The Complement System In Neurodegenerative Diseasesmentioning

confidence: 99%

The Complement System in the Central Nervous System: From Neurodevelopment to Neurodegeneration

et al. 2022

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The functions of the complement system to both innate and adaptive immunity through opsonization, cell lysis, and inflammatory activities are well known. In contrast, the role of complement in the central nervous system (CNS) which extends beyond immunity, is only beginning to be recognized as important to neurodevelopment and neurodegeneration. In addition to protecting the brain against invasive pathogens, appropriate activation of the complement system is pivotal to the maintenance of normal brain function. Moreover, overactivation or dysregulation may cause synaptic dysfunction and promote excessive pro-inflammatory responses. Recent studies have provided insights into the various responses of complement components in different neurological diseases and the regulatory mechanisms involved in their pathophysiology, as well as a glimpse into targeting complement factors as a potential therapeutic modality. However, there remain significant knowledge gaps in the relationship between the complement system and different brain disorders. This review summarizes recent key findings regarding the role of different components of the complement system in health and pathology of the CNS and discusses the therapeutic potential of anti-complement strategies for the treatment of neurodegenerative conditions.

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An “Outside-In” and “Inside-Out” Consideration of Complement in the Multiple Sclerosis Brain: Lessons From Development and Neurodegenerative Diseases

Cited by 36 publications

References 236 publications

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

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

The Role of Complement in Synaptic Pruning and Neurodegeneration

The Complement System in the Central Nervous System: From Neurodevelopment to Neurodegeneration

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