Abstract

The complement system is a key driver of neuroinflammation. Activation of complement by all pathways, results in the formation of the anaphylatoxin C5a and the membrane attack complex (MAC). Both initiate pro-inflammatory responses which can contribute to neurological disease. In this study, we delineate the specific roles of C5a receptor signaling and MAC formation during the progression of experimental autoimmune encephalomyelitis (EAE)-mediated neuroinflammation. MAC inhibition was achieved by subcutaneous administration of an antisense oligonucleotide specifically targeting murine C6 mRNA (5 mg/kg). The C5a receptor 1 (C5aR1) was inhibited with the C5a receptor antagonist PMX205 (1.5 mg/kg). Both treatments were administered systemically and started after disease onset, at the symptomatic phase when lymphocytes are activated. We found that antisense-mediated knockdown of C6 expression outside the central nervous system prevented relapse of disease by impeding the activation of parenchymal neuroinflammatory responses, including the Nod-like receptor protein 3 (NLRP3) inflammasome. Furthermore, C6 antisense-mediated MAC inhibition protected from relapse-induced axonal and synaptic damage. In contrast, inhibition of C5aR1-mediated inflammation diminished expression of major pro-inflammatory mediators, but unlike C6 inhibition, it did not stop progression of neurological disability completely. Our study suggests that MAC is a key driver of neuroinflammation in this model, thereby MAC inhibition might be a relevant treatment for chronic neuroinflammatory diseases.

Highlights

  • Neuroinflammation, or glial-cell propagated inflammation, is a broad concept describing the immune responses which are induced by inflammation or degeneration [43]

  • Systemic inhibition of membrane attack complex (MAC) or C5a receptor 1 (C5aR1) limits relapse To study the specific effect of MAC on neuroinflammation we used an antisense oligonucleotide (5 mg/kg) targeting the mRNA of complement component C6

  • We compared the effect of C6 antisense on clinical scores of mice with chronic relapsing EAE to that of PMX205 (1.5 mg/kg), an antagonist of C5aR1, thereby blocking C5aR1-mediated inflammation [47] (Fig. 1a)

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Summary

Introduction

Neuroinflammation, or glial-cell propagated inflammation, is a broad concept describing the immune responses which are induced by inflammation or degeneration [43]. Considered as ‘bystander damage’ caused by cell injury, neuroinflammation was for a long time seen as a reaction to neuronal damage. This view was recently challenged in the light of. Activation of the complement system involves various components, including C1q, mannan-binding. MAC causes cytolysis [66] or can act as an immune stimulating factor by promoting the secretion of interleukin 1 beta (IL-1β) via the Nod-like receptor protein 3 (NLRP3) inflammasome, when deposited at sub-lytic amounts [45, 78]

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