A cis-regulatory element controls expression of histone deacetylase 9 to fine-tune inflammasome-dependent chronic inflammation in atherosclerosis
What we found
Some people inherit a common DNA variant near a gene called HDAC9 that raises their risk of stroke and coronary artery disease. We traced how that variant does its damage. HDAC9 turns out to strip chemical tags off NLRP3, a sensor inside immune cells, which switches on the inflammasome and drives the cell into an inflammatory death. In mice, removing the regulatory switch that keeps HDAC9 in check made this inflammation worse. In plaque tissue taken from patients during carotid surgery, more HDAC9 went together with more advanced, less stable disease. We then packaged an HDAC-blocking drug into lipoprotein nanoparticles that home in on the inflamed vessel wall, and the plaques stabilized — pointing to a way of treating atherosclerosis as the inflammatory disease it is.
Abstract
Common genetic variants in a conserved cis-regulatory element (CRE) at histone deacetylase (HDAC)9 are a major risk factor for cardiovascular disease, including stroke and coronary artery disease. Given the consistency of this association and its proinflammatory properties, we examined the mechanisms whereby HDAC9 regulates vascular inflammation. HDAC9 bound and mediated deacetylation of NLRP3 in the NACHT and LRR domains leading to inflammasome activation and lytic cell death. Targeted deletion of the critical CRE in mice increased Hdac9 expression in myeloid cells to exacerbate inflammasome-dependent chronic inflammation. In human carotid endarterectomy samples, increased HDAC9 expression was associated with atheroprogression and clinical plaque instability. Incorporation of TMP195, a class IIa HDAC inhibitor, into lipoprotein-based nanoparticles to target HDAC9 at the site of myeloid-driven vascular inflammation stabilized atherosclerotic plaques, implying a lower risk of plaque rupture and cardiovascular events. Our findings link HDAC9 to atherogenic inflammation and provide a paradigm for anti-inflammatory therapeutics for atherosclerosis.
Topics
- HDAC9
- NLRP3 inflammasome
- Atherosclerosis
- Myeloid cells
- Cis-regulatory element
Read it
Cite
Asare Y, Yan G, Schlegl C, et al. A cis-regulatory element controls expression of histone deacetylase 9 to fine-tune inflammasome-dependent chronic inflammation in atherosclerosis. Immunity (2025). doi.org/10.1016/j.immuni.2025.01.003