Complement-mediated ‘bystander’ damage initiates host NLRP3 inflammasome activation

Abstract

Complement activation has long been associated with inflammation, primarily due to the elaboration of the complement anaphylotoxins C5a and C3a. In this work, we demonstrate that the phagocytosis of complement-opsonized particles promotes host inflammatory responses by a new mechanism that depends on the terminal complement components (C5b-C9). We demonstrate that during the phagocytosis of complement-opsonized particles, the membrane attack complex (MAC) of complement can be transferred from the activating particle to the macrophage plasma membrane by a 'bystander' mechanism. This MAC-mediated bystander damage initiates NLRP3 inflammasome activation, resulting in caspase-1 activation and IL-1β and IL-18 secretion. 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 depends on NLRP3, ASC (also known as PYCARD) and caspase-1, as macrophages deficient in any one of these components fail to secrete these cytokines following phagocytosis. The phagocytosis of complement-opsonized particles increases leukocyte recruitment and promotes T helper 17 cell (T H 17) biasing. These findings reveal a new mechanism by which complement promotes inflammation and regulates innate and adaptive immunity.

Inflammasome Priming in Sterile Inflammatory Disease

“…Recently, MAC has been suggested to provide both the priming and the activation signals for inflammasome activation because experiments indicated that MAC-mediated 'bystander' damage could lead to NLRP3 activation in mouse macrophages [48] . Specifically, this study showed that phagocytosis of complement-opsonized particles could promote inflammasome activation by a novel 'bystander' mechanism involving the transfer of MAC from the activating particle to a nearby cell.…”

Terminal complexes of the complement system: new structural insights and their relevance to function

“…An interesting recent report links the recovery processes described above with inflammasome activation; MAC internalization and incorporation into Rab5+ endosomes facilitated NF‐kB signaling through non‐canonical pathways, raising the interesting possibility that MAC continues to exert its pro‐inflammatory effects even after removal from the cell surface. In this respect, the recent description of MAC‐dependent inflammasome activation in “bystander” cells is relevant . Macrophage uptake of complement opsonized particles caused NLRP3 inflammasome activation but only when particles were opsonized in the presence of an intact terminal pathway; during this process, MAC was “transferred” to the macrophage membrane by poorly defined routes to cause sublytic damage.…”

Complement in removal of the dead – balancing inflammation

“…Thus, it will be thrilling to investigate the role of complement in other forms of cell death such as necroptosis (programmed necrosis), pyroptosis (inflammasome‐induced), or autophagic cell death. In this context, it is remarkable that sublytic membrane attack complex (MAC) is able to induce the NLRP3 inflammasome in vivo and that MAC can be transferred from complement‐opsonized particles after phagocytic uptake to the macrophage plasma membrane by a “bystander” mechanism, which finally results in inflammasome activation . The engulfment of complement‐opsonized particles results in enhanced leukocyte recruitment and promotes T helper 17 (Th17) cell biasing .…”