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Acta Neuropathol Commun. 2018 May 3;6(1):36. doi: 10.1186/s40478-018-0536-y.

Systemic inhibition of the membrane attack complex impedes neuroinflammation in chronic relapsing experimental autoimmune encephalomyelitis.

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Department of Genome Analysis, Academic Medical Center, Amsterdam, The Netherlands.
Department of Clinical Genetics, Leiden University Medical Center, Einthovenweg 20, 2333, ZC, Leiden, The Netherlands.
Department of Bioinformatics, Academic Medical Center, Amsterdam, The Netherlands.
Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.
Electron Microscopy Centre Amsterdam, Department of Medical Biology, Academic Medical Center, Amsterdam, The Netherlands.
School of Biomedical Sciences, The University of Queensland, Brisbane, Australia.
Systems Immunity University Research Institute, School of Medicine, Cardiff University, Cardiff, UK.
Department of Immunology, University of Toronto, Toronto, Canada.
Department of Clinical Genetics, Leiden University Medical Center, Einthovenweg 20, 2333, ZC, Leiden, The Netherlands.


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.


Complement; Inflammasome; Neuroinflammation

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