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The membrane attack complex as an inflammatory trigger B. Paul Morgan ∗ School of Medicine, Cardiff University, Heath Park, Cardiff CF144XN, UK

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Article history: Received 13 March 2015 Accepted 20 April 2015 Available online xxx Keywords: Complement Membrane attack Cell activation

a b s t r a c t The final common pathway of all routes of complement activation involves the non-enzymatic assembly of a complex comprising newly formed C5b with the plasma proteins C6, C7, C8 and C9. When assembly occurs on a target cell membrane the forming complex inserts into and through the bilayer to create a pore, the membrane attack complex (MAC). On some targets, pore formation causes rapid lytic destruction; however, most nucleated cell targets resist lysis through a combination of ion pumps, membrane regulators and active recovery processes. Cells survive but not without consequence. The MAC pore causes ion fluxes and directly or indirectly impacts several important signalling pathways that in turn activate a diverse series of events in the cell, many of which are highly pro-inflammatory. Although this non-lytic, pro-inflammatory role of MAC has been recognised for thirty years, no consensus signalling pathway has emerged. Recent work, summarised here, has implicated specific signalling routes and, in some cells, inflammasome involvement, opening the door to novel approaches to therapy in complement-driven pathologies. © 2015 Published by Elsevier GmbH.

Contents The membrane attack complex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sublytic MAC as an activator of target cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Signalling of sublytic effects of MAC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Complement and inflammasome activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inhibiting MAC as an anti-inflammatory strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

The membrane attack complex The membrane attack complex (MAC), the cytolytic coup de grace of complement activation, is a membrane-traversing pore formed from the five terminal pathway component proteins. It is a member of a large and heterogeneous group of pore-forming proteins that play roles in attack and defence in organisms from bacteria to man (Rosado et al., 2008; Iacovache et al., 2008; Gilbert et al., 2014). All in this diverse group share the capacity to create physical or functional pores that breach biological membranes, but the pore structures vary considerably. Two pore-forming protein complexes play important roles in mammalian immunity; perforin,

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a protein present in granules of cytolytic T cells and NK cells that binds target membranes and oligomerises to form pores, and the MAC (Kondos et al., 2010). There are numerous structural and functional similarities between these immune effectors that are beyond the scope of this brief review. MAC assembly begins with cleavage of C5 by a C5 convertase enzyme of the classical/lectin (C4b2a3b) or alternative (C3bBbC3b) pathways (Pangburn and Rawal, 2002). This cleavage is the final enzymatic event in the complement pathway and the first step in the terminal pathway (Müller-Eberhard, 1985; Esser, 1994). The biologically potent pro-inflammatory peptide C5a is released, leaving the large C5b fragment still attached to its parent enzyme. Nascent C5b binds the plasma proteins C6 and C7, triggering a conformational change that releases the tri-molecular C5b67 complex to the fluid phase and creates a labile hydrophobic membrane binding site in the complex. The large majority of C5b67 complexes formed decay in the fluid phase through hydrolysis of the

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membrane binding site and/or binding fluid-phase inhibitors that include clusterin, vitronectin and, notably, C8 – the next component in the sequence. Those fortunate few that encounter membrane before the binding site decays or is blocked by protein inhibitors, lock tightly onto the membrane. Bound C5b67 sequentially recruits C8 and multiple copies of C9 from plasma, and induces major conformational change in these molecules, unfolding and aggregating as the complex embeds more deeply into the membrane, finally creating a transmembrane pore containing one molecule each of C5b, C6, C7 and C8 with as many as twelve C9 molecules, these forming the walls of the MAC pore (Podack and Tschopp, 1984). MAC assembly in the membrane is regulated by CD59, a 20 kDa glycolipid-anchored protein that binds tightly into the forming MAC at the C5b-8 stage and prevents further recruitment of C9 into the complex – thereby preventing pore formation (Davies and Lachmann, 1993). CD59 is broadly expressed on human cells and in all mammalian species studied. Sublytic MAC as an activator of target cells The MAC has evolved to deliver lytic killing of pathogens; indeed, deficiencies of MAC component proteins predispose to infection, albeit only for Neisseria species infections (Ram et al., 2010). When complement is activated on self-cells, multiple defence mechanisms and regulators limit MAC assembly and accelerate MAC removal from the membrane (Morgan, 1989). Self-cells are thus protected from lytic killing in all but the most extreme circumstances. CD59 on the cell surface restricts pore formation but, because it is a suicide inhibitor consumed in the act of inhibition, may become depleted. Pores that do form in the membrane cause inward leakage of water and ions – events that in metabolically inert targets, such as aged erythrocytes, progress to lysis but in nucleated cells are countered by ion pumps. Pumps consume energy and can be overwhelmed if inward leakage continues; however, nucleated cells also actively remove MAC lesions from the membrane, either by budding off (ectocytosis) or engulfment (endocytosis). MAC lesions are thus transient, allowing cells to survive. Assembly of pores at sublytic levels in nucleated cell membranes is not without consequence; many different effects have been described in different cell types, including on cell cycle and proliferation (either enhancing or inhibiting), apoptosis (accelerating or delaying), protein synthesis, membrane lipid composition, granule release etc. (Morgan, 1992; Cole and Morgan, 2003; Elimam et al., 2013; Takano et al., 2013). Proinflammatory consequences of sublytic MAC have been reported in many cell types. Neutrophils (and macrophages) were induced to synthesise and secrete inflammatory cytokines and triggered to degranulate, releasing their arsenal of inflammatory mediators (Morgan, 1992). Sublytic MAC triggered mesangial cells and microglia to release inflammatory cytokines (Zhang et al., 2014; Yang et al., 2014). Retinal epithelial cells exposed to sublytic MAC were stimulated to release IL-6, IL-8, MCP-1, and VEGF (Lueck et al., 2011). Platelet activation by MAC in the absence of lysis is described in many reports; effects include release of microparticles and surface changes causing increased stickiness (Martel et al., 2011). Signalling of sublytic effects of MAC Among the ions entering the cell, Ca2+ is particularly relevant to downstream effects because of the large concentration gradient and the importance of intracellular Ca2+ concentration ([Ca2+ ]i) as a first signal for cell activation. Ca2+ influx through the pore increases [Ca2+ ]i that in turn triggers Ca2+ -activated Ca2+ release from endoplasmic reticulum stores; as a result, [Ca2+ ]i

Fig. 1. MAC pathways to cell activation and inflammation. The MAC pore permits Ca2+ influx thereby increasing intracellular Ca2+ concentration ([Ca2+ ]i). Elevated cytosolic [Ca2+ ]i triggers the opening of Ca2+ channels in the endoplasmic reticulum (ER) and release of Ca2+ from stores, further elevating [Ca2+ ]i. Calmodulin (CaM) is activated by increased [Ca2+ ]i and switches on multiple downstream proteases, including Akt and PI3k (phosphatidylinositol-3-kinase), that in turn trigger multiple downstream effectors of inflammation and other activation events. Increased [Ca2+ ]i also triggers assembly and activation of the NLRP3 inflammasome with resultant cleavage of the pro-forms of the inflammatory cytokines IL-8 and IL-1␤ to generate the active, secreted cytokines. MAC may also cause cell activation through interactions with other signalling molecules in the membrane. Association with G-protein-coupled receptors may enable MAC to engage cAMP (cyclic adenosine monophosphate)-mediated activation pathways. Clustering with the GPI-anchored MAC regulator CD59 may trigger GPI-associated G-proteins and phospholipases that generate IP3 (inositol-3-phosphate) with resultant opening of Ca2+ channels in the plasma membrane and ER and activation of downstream effectors.

increases from low nanomolar resting levels into the micromolar range within seconds (Morgan, 1989). Increased [Ca2+ ]i engages intracellular signalling pathways by binding multiple cytoplasmic Ca2+ binding proteins, notably calmodulin. When [Ca2+ ]i exceeds a critical threshold, Ca2+ ions bind calmodulin, triggering major conformational changes that enable activation of downstream calmodulin-dependent kinases to drive events in the cell (Fig. 1). Although the prevailing evidence supports the concept that [Ca2+ ]i, through engagement of Ca2+ -dependent signalling pathways is the principle mediator of sublytic MAC effects, MAC induces activation in some cell types even when Ca2+ influx is prevented by removal of extracellular Ca2+ and/or intracellular Ca2+ chelation. A direct interaction of the MAC with the Gi␣-subunit, classically linked to G-protein-coupled receptor family members, has been described (Niculescu et al., 1997), providing a possible Ca2+ independent route to regulation of cyclic AMP (cAMP) production. Precisely how MAC, formed from five plasma proteins with no obvious G-protein binding motifs, intercalates with the Gi␣-subunit and other signal transducers in the membrane is unresolved. The recent emergence of evidence showing that MAC interacts functionally and physically with toll receptors, GPCRs and other signalling receptors in the membrane provides a possible explanation (Liu et al., 2011; Mastellos et al., 2013). No structure/function explanation has yet emerged for these MAC interactions, although it has been suggested that MAC localises to the same membrane microdomains as these receptors (Morgan et al., 1987; Hänsch 1992; Dunstone and Tweten, 2012). The membrane regulator of MAC assembly, CD59, has been implicated in MAC signalling. CD59 is a glycosyl phosphoinositol lipid (GPI)-anchored protein and, in common with other GPIanchored proteins, has the capacity to signal when cross-linked

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(Horejsí et al., 1999; Matkó et al., 2002). GPI-anchored proteins cluster on cell surfaces in lipid microdomains that also associate with cytoplasmic signalling molecules, including Src family kinases, and G-proteins together with adaptor proteins that link these entities (Horejsí et al., 1999). Cross-linking of CD59 with antibody re-orientates these microdomain components to trigger cell activation events (van den Berg et al., 1995). During sublytic attack, CD59 becomes tightly bound into the forming MAC, clustering on the cell surface. It is possible, though unproven, that this MAC/CD59 clustering delivers cell activation signals in the same way as antibody cross-linking of CD59. Numerous downstream signalling pathways have been implicated in many studies of sublytic MAC effects on different cell types and with different complement sources; lacking is any single core pathway. Nevertheless, common pathways do emerge from multiple studies in diverse target cells, notably the PI3kinase, Akt/FOX01 and ERK1 pathways (Fosbrink et al., 2006; Ren et al., 2008; Qiu et al., 2012). We recently undertook an unbiased comparison of gene expression in MAC-attacked and control tumor cells; ERK1 emerged as a central signalling node, supporting its critical role in MAC signalling. MAC-dependent activation of the cyclin-dependent kinases (CDKs) 2 and 4 has been described, leading to cell activation and proliferation (Tegla et al., 2011). MAC triggering of apoptotic pathways through BCP-2-associated death receptor (Bad) phosphorylation leading to caspase activation has been described in multiple cell types (Hila et al., 2001; Tegla et al., 2011).

Complement and inflammasome activation Inflammasomes are oligomeric signalling platforms present in diverse cell types that integrate multiple signals from pathogen recognition molecules and other “danger” detectors to deliver an appropriately targeted inflammatory response. The NLRP3 inflammasome has been most studied in the context of inflammation because of its broad distribution and capacity to respond to numerous triggers. NLRP3 inflammasome triggering causes activation of caspase-1 that in turn leads to the maturation and secretion of IL-1␤ and IL-18. In innate immune cells, this pathway plays a central role in switching on both inflammation and apoptotic cell death (Horng, 2014). Increased intracellular Ca2+ and resultant mitochondrial injury have been implicated as mediators of inflammasome activation. This key role of Ca2+ led us to investigate whether sublytic MAC, a potent trigger to increased [Ca2+ ]i, could trigger inflammasome activation. Sublytic MAC triggered NLRP3 inflammasome assembly and activation in LPS-primed lung epithelial cells. Confocal imaging demonstrated MAC-dependent co-localisation of the component proteins and biochemical assays showed caspase activation and IL-1␤ production (Triantafilou et al., 2013). Increased [Ca2+ ]i, both through influx via the MAC pore and release from stores, was an early and key event that also triggered mitochondrial damage and apoptotic pathways in the cells. In a separate study, exposure of murine dendritic cells to sub-lytic MAC triggered NLRP3 inflammasome activation and production of IL-1␤ and IL-18 (Laudisi et al., 2013). These findings were recapitulated in vivo where inflammasome activation in LPS-treated mice, assessed by measuring plasma IL-1␤ and IL-18, was markedly reduced in C6deficient mice (unable to make MAC) and in wild-type mice given MAC-blocking antibodies. These data provided strong support for the proposition that sublytic MAC triggers inflammation in vivo primarily through inflammasome activation; by extension, it can be argued that drugs targeting the inflammasome, caspases or IL-1␤ would be effective in MAC-driven pathologies. Both C3a and C5a have also been implicated in inflammasome activation in some cell types. In LPS-primed human macrophages,

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DCs and monocytes, C3a was a potent second signal for NLRP3 inflammasome activation, assessed by measuring IL-1␤ production, (Asgari et al., 2013). Although the precise pathway by which C3a caused inflammasome activation was not fully elucidated, it included C3aR engagement of ERK signalling pathways and regulation of ATP levels. Critically, these events increased the induction of pro-inflammatory Th17 cells in mixed cultures. Cholesterol crystals, a hallmark of atherosclerosis, are among many particulate triggers of inflammasome activation (Rajamäki et al., 2010). A role for C5a in this process was recently proposed based on the observation that cholesterol crystals spontaneously activated complement and inhibition of complement activation removed the capacity of crystals to activate the inflammasome (Samstad et al., 2014). C5-depleted serum was inactive in these studies, leading the authors to focus attention on C5a; however, a role for MAC as a trigger was not explored. Regardless, the data suggested that cholesterol crystal-induced inflammasome activation and inflammation in atherosclerosis requires complement triggers and may be treatable with anti-complement drugs.

Inhibiting MAC as an anti-inflammatory strategy The data described above demonstrate that the MAC is a potent activator of cells and an important driver of inflammation. Further evidence of its relevance to inflammatory pathologies is provided by numerous studies in disease models where inability to make MAC is protective. Nature has provided the tools in the form of strains of rabbits, rats and mice that are deficient in C6, an essential component of the MAC. C6-deficient animals show reduced or absent disease in models of inflammatory disease spanning many organ systems. For example, rats and mice deficient in C6 fail to develop disease in acute brain inflammation models and in models of the neuromuscular conduction disorder myasthenia gravis (Mead et al., 2002; Morgan et al., 2006). Drugs that inhibit MAC might therefore have broad applications. A major advantage of targeting MAC is that opsonisation, the major antibacterial activity of complement, is unaffected so infection risk is restricted to the few organisms that are killed by MAC (critically, Neisseria species). The anti-C5 mAb Eculizumab, the first such drug in the clinic, blocks MAC formation by binding C5 and preventing its cleavage by the C5 convertase. Originally developed for treatment of paroxysmal nocturnal hemoglobinuria (Schrezenmeier and Höchsmann, 2009), Eculizumab is now in or near the clinic for numerous and diverse inflammatory diseases (Wong and Kavanagh, 2015), and many other C5-targeting drugs are in company pipelines. Blocking C5 cleavage will stop production of C5a as well as MAC and this may have unwanted consequences if continued long term, for example, effects on tissue healing (Iyer et al., 2011). Agents that specifically target MAC may be just as effective in inflammatory disease and there are multiple potential targets downstream of C5 cleavage. Preclinical studies have explored the use of agents that mimic the natural fluid-phase and membrane MAC inhibitors, or have targeted individual MAC component proteins beyond C5. Blocking antibodies and anti-sense knockdown targeting C6 or other components has been shown to inhibit inflammation in models (Fluiter et al., 2014), and small molecule MAC blockers have been described (Lee et al., 2014). An alternative approach to controlling MAC-driven inflammation is to inhibit the downstream signalling pathways described above. As more certainty accumulates regarding the precise mechanisms of inflammation induction, such agents may emerge, providing an even safer therapeutic avenue that does not threaten the anti-bacterial lytic activities of MAC.

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Concluding remarks The data implicating MAC as an inflammatory mediator driving pathology in many diseases are now overwhelming. The evidence shows that MAC behaves as a critical danger signal, collaborating with other danger signals delivered by pattern recognition receptors to engage multiple inflammatory pathways in target cells. Removing MAC in many inflammatory disease models reduces or eliminates disease. Current anti-complement therapies, notably Eculizumab, likely work in inflammatory diseases through inhibiting these MAC effects. New drugs specifically targeting MAC or the downstream inflammatory pathways that it engages will emerge over the coming years and MAC inhibition will likely become a common clinical intervention in inflammation. Conflict of interest None declared. References Asgari, E., Le Friec, G., Yamamoto, H., Perucha, E., Sacks, S.S., Köhl, J., Cook, H.T., Kemper, C., 2013. C3a modulates IL-1␤ secretion in human monocytes by regulating ATP efflux and subsequent NLRP3 inflammasome activation. Blood 122, 3473–3481, http://dx.doi.org/10.1182/blood-2013-05-502229 Cole, D.S., Morgan, B.P., 2003. Beyond lysis: how complement influences cell fate. Clin. Sci. (Lond.) 104, 455–466. Davies, A., Lachmann, P.J., 1993. Membrane defence against complement lysis: the structure and biological properties of CD59. Immunol. Res. 12, 258–275. Dunstone, M.A., Tweten, R.K., 2012. Packing a punch: the mechanism of pore formation by cholesterol dependent cytolysins and membrane attack complex/perforin-like proteins. Curr. Opin. Struct. Biol. 22, 342–349, http://dx. doi.org/10.1016/j.sbi.2012.04.008 Elimam, H., Papillon, J., Takano, T., Cybulsky, A.V., 2013. Complement-mediated activation of calcium-independent phospholipase A2␥: role of protein kinases and phosphorylation. J. Biol. Chem. 288, 3871–3885, http://dx.doi.org/10.1074/jbc. M112.396614 Esser, A.F., 1994. The membrane attack complex of complement. Assembly, structure and cytotoxic activity. Toxicology 87, 229–247. Fluiter, K., Opperhuizen, A.L., Morgan, B.P., Baas, F., Ramaglia, V., 2014. Inhibition of the membrane attack complex of the complement system reduces secondary neuroaxonal loss and promotes neurologic recovery after traumatic brain injury in mice. J. Immunol. 192, 2339–2348. Fosbrink, M., Niculescu, F., Rus, V., Shin, M.L., Rus, H., 2006. C5b-9-induced endothelial cell proliferation and migration are dependent on Akt inactivation of forkhead transcription factor FOXO1. J. Biol. Chem. 281, 19009–19018. Gilbert, R.J., Dalla Serra, M., Froelich, C.J., Wallace, M.I., Anderluh, G., 2014. Membrane pore formation at protein–lipid interfaces. Trends Biochem. Sci. 39, 510–516, http://dx.doi.org/10.1016/j.tibs.2014.09.002 Hänsch, G.M., 1992. The complement attack phase: control of lysis and non-lethal effects of C5b-9. Immunopharmacology 24, 107–117. Hila, S., Soane, L., Koski, C.L., 2001. Sublytic C5b-9-stimulated Schwann cell survival through PI 3-kinase-mediated phosphorylation of BAD. Glia 36, 58–67. ´ J., Brdicka, T., Angelisová, P., Stockinger, Horejsí, V., Drbal, K., Cebecauer, M., Cerny, H., 1999. GPI-microdomains: a role in signalling via immunoreceptors. Immunol. Today 20, 356–361. Horng, T., 2014. Calcium signaling and mitochondrial destabilization in the triggering of the NLRP3 inflammasome. Trends Immunol. 35, 253–261, http://dx.doi. org/10.1016/j.it.2014.02.007 Iacovache, I., van der Goot, F.G., Pernot, L., 2008. Pore formation: an ancient yet complex form of attack. Biochim. Biophys. Acta 1778, 1611–1623, http://dx.doi. org/10.1016/j.bbamem.2008.01.026 Iyer, A., Woodruff, T.M., Wu, M.C., Stylianou, C., Reid, R.C., Fairlie, D.P., Taylor, S.M., Brown, L., 2011. Inhibition of inflammation and fibrosis by a complement C5a receptor antagonist in DOCA-salt hypertensive rats. J. Cardiovasc. Pharmacol. 58, 479–486, http://dx.doi.org/10.1097/FJC.0b013e31822a7a09 Kondos, S.C., Hatfaludi, T., Voskoboinik, I., Trapani, J.A., Law, R.H., Whisstock, J.C., Dunstone, M.A., 2010. The structure and function of mammalian membraneattack complex/perforin-like proteins. Tissue Antigens 76, 341–351, http://dx. doi.org/10.1111/j.1399-0039.2010.01566.x Laudisi, F., Spreafico, R., Evrard, M., Hughes, T.R., Mandriani, B., Kandasamy, M., Morgan, B.P., Baalasubramanian, S., Mortellaro, A., 2013. Cutting edge: the NLRP3 inflammasome links complement-mediated inflammation and IL-1␤ release. J. Immunol. 191, 1006–1010. Lee, M., Narayanan, S., McGeer, E.G., McGeer, P.L., 2014. Aurin tricarboxylic acid protects against red blood cell hemolysis in patients with paroxysmal nocturnal hemoglobinemia. PLoS ONE 9 (1), e87316, http://dx.doi.org/10.1371/journal. pone.0087316 Liu, J., Jha, P., Lyzogubov, V.V., Tytarenko, R.G., Bora, N.S., Bora, P.S., 2011. Relationship between complement membrane attack complex, chemokine (C–C motif) ligand

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Wong, E.K., Kavanagh, D., 2015. Anticomplement C5 therapy with eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Transl. Res. 165, 306–320, http://dx.doi.org/10.1016/j.trsl.2014. 10.010 Yang, C., Yang, L., Liu, Y., 2014. Soluble complement complex C5b-9 promotes microglia activation. J. Neuroimmunol. 267, 16–19, http://dx.doi.org/10.1016/ j.jneuroim.2013.11.007

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Please cite this article in press as: Morgan, B.P., The membrane attack complex as an inflammatory trigger. Immunobiology (2015), http://dx.doi.org/10.1016/j.imbio.2015.04.006

The membrane attack complex as an inflammatory trigger.

The final common pathway of all routes of complement activation involves the non-enzymatic assembly of a complex comprising newly formed C5b with the ...
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