Complement Membrane Attack Complex

Abstract

The complement membrane attack complex (MAC) is classically known as a cytolytic effector of innate and adaptive immunity that forms pores in the plasma membrane of pathogens or targeted cells, leading to osmolysis. Nucleated cells resist MAC-mediated cytolysis by expression of inhibitors that block MAC assembly or by rapid removal of MAC through endocytosis or shedding. In the absence of lysis, MAC may induce intracellular signaling and cell activation, responses implicated in a variety of autoimmune, inflammatory, and transplant disease settings. New discoveries into the structure and biophysical properties of MAC revealed heterogeneous MAC precursors and conformations that provide insights into MAC function. In addition, new mechanisms of MAC-mediated signaling and its contribution to disease pathogenesis have recently come to light. MAC-activated cells have been found to express proinflammatory proteinsdoften through NF-kBedependent transcription, assemble inflammasomes, enabling processing, and facilitate secretion of IL-1b and IL-18, as well as other signaling pathways. These recent insights into the mechanisms of action of MAC provide an updated framework to therapeutic approaches that can target MAC assembly, signaling, and proinflammatory effects in various complement-mediated diseases.

Chronic complement dysregulation drives neuroinflammation after traumatic brain injury: a transcriptomic study

“…Hence, inhibition of C5a production by CR2-Crry may be a contributing factor to decreased immune cell infiltration/activation, and subsequently C1q expression by immune cells resulting in decreased C1q-mediated polarization of reactive astrocytes to the neurotoxic A1 subtype [ 20 , 47 ]. We cannot exclude the possibility that decreased activation of immune and astroglial cells may be at least partially mediated by the inhibitory effect of CR2-Crry on membrane attack complex (MAC) formation, which could otherwise induce cell lysis and the release of pro-inflammatory cytokines, damage-associated molecular patterns, and excitotoxic glutamate [ 48 ]. However, data from our group have shown that specific inhibition of MAC formation in a therapeutic paradigm is not protective in the chronic phase after severe TBI, unlike inhibiting C3 activation [ 12 ].…”

Complement in trauma—Traumatised complement?

“…This leads downstream to the formation of the C5 convertases C4b2a3b and C3bBb3b, which activate the terminal pathway through the cleavage of C5 into the anaphylatoxin C5a and C5b, which represents the starting point for the membrane attack complex C5b-9 (Figure 1) (for review, see Hajishengallis, Reis, Mastellos, Ricklin, & Lambris, 2017;Ricklin, Hajishengallis, Yang, & Lambris, 2010). Upon membrane attack complex generation, which morphologically forms a membrane pore, the targeted cell is lysed and killed, while sublytic concentrations of the complex can facilitate intracellular signalling and cell activation, for instance a NF-κB-dependent transcription of IL-8 on endothelial cells (for detailed review, see Xie, Jane-Wit, & Pober, 2020). Like its upstream relative C3a, C5a also acts as a small signalling molecule by its binding to two different receptors, C5a 1 (CD88) and C5a 2 (C5L2).…”

TPC2 promotes choroidal angiogenesis and inflammation in a mouse model of neovascular age-related macular degeneration

“…Activation of the complement system plays a key role in the pathogenesis of neovascular AMD. In particular, assembly of the membrane attack complex (MAC) that triggers downstream activation of the Nod-like receptor protein 3 inflammasome is considered a major factor in the inflammatory reaction of AMD ( 30 ). In agreement with this model, a clear signal for the terminal complement complex C5b-9 that forms MAC could be detected in lesion areas of WT mice ( Fig 4B , upper panel).…”