The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response

Abstract

NLRP3 inflammasome assembly activates caspase-1 and mediates the processing and release of the leaderless cytokine IL-1β, and thereby plays a central role in the inflammatory response and in diverse human diseases. Here we report that upon caspase-1 activation oligomerized NLRP3-inflammasome particles are released from macrophages. Recombinant oligomeric protein particles composed of the adapter protein ASC or the cryopyrin-associated periodic syndromes (CAPS) mutant NLRP3 p.D303N, stimulate further caspase-1 activation extracellularly, and also intracellularly upon phagocytosis by surrounding macrophages. ASC oligomeric particles were found in the serum of patients with active CAPS, but not in patients with other inherited autoinflammatory diseases. Our findings support a model whereby the NLRP3-inflammasome, acting as an extracellular oligomeric complex, amplifies the inflammatory response.