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

TLDR

The complement system is a key innate immune component whose dysregulation contributes to autoimmune and inflammatory diseases, often associated with elevated IL‑1β. The study investigates how complement activates IL‑1β secretion in murine dendritic cells. Complement activates IL‑1β and IL‑18 secretion through the NLRP3 inflammasome in murine dendritic cells, a process dependent on NLRP3, ASC, and caspase‑1, and driven by sublethal MAC rather than C3a/C5a, indicating IL‑1β as a therapeutic target for complement‑mediated inflammation.

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.