B: MAC can induce signaling independent of membrane pore formation. A: On complement activation, MAC deposition, and insertion into the plasma membrane, MAC can induce downstream prolytic and prosurvival, proliferative, and proinflammatory pathways that are dependent on MAC functioning as a pore and allowing small-molecule or ion flux, including potassium (K +) efflux, ATP entry, or calcium (Ca 2+) influx. 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.įigure 2 Membrane attack complex (MAC)–initiated intracellular signaling pathways lead to altered cell functions and cell activation. MAC-activated cells have been found to express proinflammatory proteins-often through NF-κB–dependent transcription, assemble inflammasomes, enabling processing, and facilitate secretion of IL-1β and IL-18, as well as other signaling pathways. In addition, new mechanisms of MAC-mediated signaling and its contribution to disease pathogenesis have recently come to light. New discoveries into the structure and biophysical properties of MAC revealed heterogeneous MAC precursors and conformations that provide insights into MAC function. 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. Nucleated cells resist MAC-mediated cytolysis by expression of inhibitors that block MAC assembly or by rapid removal of MAC through endocytosis or shedding. 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.
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