The C3a receptor, caspase-1, and release of IL-1β.
In this issue of Blood, Asgari et al report that engagement of the C3a receptor triggers interleukin-1b (IL-1b) processing and release via caspase-1 activation. The role of complement activation in IL-1 production has a long history; complement products function as "alarmins" during innate responses. For many years before the term “innate immune response” was coined, it was fully understood that a highly nonspecific event such as activation of complement would induce a highly nonspecific molecule such as IL-1; these 2 linked processes would then affect a highly specific event such antigen-driven lymphocyte activation, for example, polarization to a T helper 1 (Th1) or a Th17 response. In this issue, investigators link the generation of C3a to playing a role in the activation of caspase-1. A unique and unexpected finding of the study is that engagement of the C3a receptor results in phosphorylation of extracellular signal-regulated kinase-1 and 2 (ERK-1/2), which promotes the efflux of adenosine triphosphate (ATP) from the macrophage. Release of ATP is a rate-limiting step for activating caspase-1, as extracellular ATP triggers the P2X7 purinergic receptor to initiate oligomerization of NLRP3.
UNIVERSITY OF COLORADO DENVER;
Charles A
CA
Dinarello
D000255:Adenosine Triphosphate / Q000378:metabolism*; D002352:Carrier Proteins / Q000502:physiology*; D003176:Complement C3 / Q000502:physiology*; D006801:Humans; D058847:Inflammasomes / Q000502:physiology*; D053583:Interleukin-1beta / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein
C038245:C3 protein, human; D002352:Carrier Proteins; D003176:Complement C3; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D000255:Adenosine Triphosphate