Cutting Edge: The NLRP3 Inflammasome Links Complement-Mediated Inflammation and IL-1β Release

Abstract

The complement system is a potent component of the innate immune response, promoting inflammation and orchestrating defense against pathogens. However, dysregulation of complement is critical to several autoimmune and inflammatory syndromes. Elevated expression of the proinflammatory cytokine IL-1β is often linked to such diseases. In this study, we reveal the mechanistic link between complement and IL-1β secretion using murine dendritic cells. IL-1β secretion occurs following intracellular caspase-1 activation by inflammasomes. We show that complement elicits secretion of both IL-1β and IL-18 in vitro and in vivo via the NLRP3 inflammasome. This effect depends on the inflammasome components NLRP3 and ASC, as well as caspase-1 activity. Interestingly, sublethal complement membrane attack complex formation, but not the anaphylatoxins C3a and C5a, activated the NLRP3 inflammasome in vivo. These findings provide insight into the molecular processes underlying complement-mediated inflammation and highlight the possibility of targeting IL-1β to control complement-induced disease and pathological inflammation.

Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-beta production and axonal degeneration-associated Caspase-6 activation

“…Another difference is that Ramaswamy et al, 37 cultured their cells in 10% serum whereas we used 5% decomplemented serum. It has been reported that complement can activate the NLRP3 inflammasome in dendritic cells 46 and a similar mechanism in primary human neurons would explain the difference between our results. Nevertheless, as each inflammasome is activated by specific DAMPs and PAMPs, these results suggest that human neurons, astrocytes, and microglia are equipped to launch a differential response to inflammasome activating agents.…”

Inflammasome Priming in Sterile Inflammatory Disease

“…In particular, it has been demonstrated that sublytic MAC can trigger increased Ca 2+ and, in turn, NLRP3 activation in primary human lung epithelial cells [45] . Moreover, MAC activation seems to be indispensable for NLRP3-mediated IL-1 production because mice lacking complement protein C6, which have an impaired terminal MAC pathway, are not able to activate the inflammasome [46] . In addition, targeted deletion of complement component 9 (C9) leads to decreased IL-1 production in a mouse model of LPS-induced inflammation, suggesting that C5b-9 might play a role in inflammasome priming or activation [47] .…”

Complement Factor 3 Is Associated With Insulin Resistance and With Incident Type 2 Diabetes Over a 7-Year Follow-up Period: The CODAM Study

“…C3 is the central component of the complement system, and activation via any of the three major complement pathways results in cleavage of C3 into C3a and C3b and subsequent activation of the terminal complement pathway with concurrent formation of C5a and C5b-C9 (also known as the membrane attack complex) (7). Both the anaphylatoxins C3a and C5a, by acting on their respective receptors, and the (sublytic) membrane attack complex have been shown to induce inflammatory responses (8)(9)(10)(11)(12).…”