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

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.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0536-y) contains supplementary material, which is available to authorized users.

Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease

“…Complement genes are necessary for the generation of anaphylatoxins C3a and C5a, opsonisation of pathogens, and formation of the membrane attack complex [39]. Inhibition of the complement system has been shown to reduce the expression of inflammatory mediators, and promote the activation of anti-inflammatory pathways, including the LXR and PPAR nuclear receptor pathways, halting neuroinflammation in the chronic relapsing EAE model [149]. Anaphylatoxins C3a and C5a bind to their corresponding membrane-bound receptors (C3aR, C5aR1 and C5aR2) on the surface of monocytes and macrophages regulating the aggregation of the inflammasome (Fig 3).…”

Calcium Influx through Plasma-Membrane Nanoruptures Drives Axon Degeneration in a Model of Multiple Sclerosis

“…Similarly, secreted phospholipases, which are expressed by immune cells in MS and EAE lesions, could directly attack the plasma membrane (Kalyvas et al., 2009). Finally, the immune system employs a well-defined armamentarium of pore-forming proteins, such as the membrane attack complex, which is formed as part of the terminal complement pathway—a pathway that has been shown to be activated in both MS and a related animal model (Watkins et al., 2016, Michailidou et al., 2018) . Perforin is another pore-forming protein that is released from cytotoxic granules of CD8 + T and natural killer (NK) cells, which has been implicated as a mediator of autoimmune-mediated attacks on oligodendrocytes, as well as on axons (Deb et al., 2009).…”

Complement in neurological disorders and emerging complement-targeted therapeutics

“…In experimental autoimmune encephalomyelitis (EAE), a widely used rodent model of MS, C6-deficient animals are protected from demyelination, highlighting the role of MAC in acute demyelination 105 . In addition, systemic inhibition of MAC in an EAE model by use of an antisense oligonucleotide that targets C6 prevented disease relapse and protected the animals from axonal and synaptic damage 106 . These observations are especially relevant to ADEM, an acute demyelinating syndrome that is often associated with myelin oligodendrocyte glycoprotein (MOG) antibodies, because MOG is localized to the outer myelin lamellae and so is readily accessible to complement.…”