The Complement System is an important component of innate immunity,

whose activation has been associated with acute inflammation. Activation of

complement leads to the generation of a Membrane Attack Complex (MAC)

composed of C5b-C9 proteins. The function of the MAC has been primarily

associated with target cell death through the polymerization and insertion of C9 on

the surface of complement activating particles. Here, I provide evidence that MAC

assembled on the surface of complement activating particles, can be transferred to

host macrophages during the process of phagocytosis. This “bystander activation”

onto macrophages causes potassium efflux and ROS production, which induces the

assembly of the NLRP3 inflammasome, which in turn results in the activation of

caspase-1 and the processing and secretion of IL-1β and IL-18 to regulate both

innate and adaptive immunity. Inflammasome activation is not induced when

macrophages phagocytize unopsonized particles or particles opsonized with serum

deficient in one of the terminal complement components. The secretion of IL-1β

and IL-18 by macrophages is dependent on NLRP3, ASC, and caspase-1, as

macrophages deficient in any one of these components fail to secrete these

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cytokines following complement-mediated phagocytosis. The phagocytosis of

complement-opsonized particles increases leukocyte recruitment and promoted

Th17 biasing.

Leishmania major, an intracellular pathogen, follows a similar pattern,

when infecting macrophages: Phagocytosis of the pathogen was accompanied by

the activation of complement pathway resulting in “bystander activation” and

NLRP3 inflammasome assembly. When macrophages are primed with IFN and

IL-1β together prior infection, the killing of parasites is enhanced demonstrating

that IL-1β can work in concert with IFNγ to activate macrophages and thus reduce

the intracellular burden of the pathogen. This study demonstrates that the

phagocytosis of complement-opsonized particles can induce inflammasome

activation by a novel mechanism involving MAC-mediated “bystander activation”

of host macrophages. This work provides another mechanism whereby

complement activation can lead to acute inflammation and identifies a previously

undescribed function of the MAC to activate inflammasomes on macrophages.