NLRP3 Inflammasome Activity Is Negatively Controlled by miR-223

TLDR

Inflammasomes are multiprotein platforms that activate caspase‑1 and trigger pyroptosis, with NLRP3 acting as a key sensor of cellular stress and uniquely subject to transcriptional regulation. The study identifies the myeloid‑specific microRNA miR‑223 as a critical regulator of NLRP3 inflammasome activity. miR‑223 binds a conserved site in the NLRP3 3′UTR to suppress its expression, thereby lowering inflammasome activity, and its variable expression across myeloid cell types positions it as a rheostat for NLRP3 regulation.

Abstract

Abstract Inflammasomes are multiprotein signaling platforms that form upon sensing microbe- or damage-associated molecular patterns. Upon their formation, caspase-1 is activated, leading to the processing of certain proinflammatory cytokines and the initiation of a special type of cell death, known as pyroptosis. Among known inflammasomes, NLRP3 takes on special importance because it appears to be a general sensor of cell stress. Moreover, unlike other inflammasome sensors, NLRP3 inflammasome activity is under additional transcriptional regulation. In this study, we identify the myeloid-specific microRNA miR-223 as another critical regulator of NLRP3 inflammasome activity. miR-223 suppresses NLRP3 expression through a conserved binding site within the 3′ untranslated region of NLRP3, translating to reduced NLRP3 inflammasome activity. Although miR-223 itself is not regulated by proinflammatory signals, its expression varies among different myeloid cell types. Therefore, given the tight transcriptional control of NLRP3 message itself, miR-223 functions as an important rheostat controlling NLRP3 inflammasome activity.