Genome-wide association studies have identified HDAC9, which encodes histone deacetylase 9, as a major risk locus for cardiovascular disease. Asare et al. now report that the targeted deletion of a conserved cis-regulatory element (CRE) in mouse Hdac9 leads to increased Hdac9 expression, which in turn increases NLRP3 inflammasome activation. In mouse models of atherosclerosis, HDAC9-mediated activation of the NLRP3 inflammasome exacerbates chronic inflammation and the authors show that targeting HDAC9 in myeloid cells can protect against atherosclerotic disease.

The increased levels of IL-1β and IL-18 seen after Hdac9 CRE deletion suggested a role for the inflammasome. In agreement with this, bone marrow-derived macrophages (BMDMs) from Hdac9ΔCREApoe−/− mice had higher levels of cleaved caspase-1 compared with BMDMs from Apoe−/− mice after treatment with inflammasome activators. Moreover, BMDMs from either Hdac9−/−Apoe−/− or Apoe−/− mice treated with TMP195 (an HDAC inhibitor with high affinity for HDAC9) showed decreased caspase-1 cleavage and reduced gasdermin D-driven pyroptosis. The increase in atherosclerotic disease seen in the Hdac9ΔCREApoe−/− mice could also be reversed when these mice were treated with the NLRP3 inhibitor MCC950. Therefore, NLRP3 inflammasome activation is central to the increased vascular inflammation seen in mice lacking the Hdac9 CRE.