Macrophage–NLRP3 Activation Promotes Right Ventricle Failure in Pulmonary Arterial Hypertension

作者：Ruaa Al‐Qazazi, Patrícia Lima, Sasha Z. Prisco, François Potus, Asish Dasgupta, Kuang‐Hueih Chen, Lian Tian, Rachel E. T. Bentley, Jeff Mewburn, Ashley Y Martin, Danchen Wu, Oliver W. Jones, Donald H. Maurice, Sébastien Bonnet, Steeve Provencher, Kurt W. Prins, Stephen L. Archer · 发表于：American Journal of Respiratory and Critical Care Medicine · 年份：2022 · DOI：10.1164/rccm.202110-2274oc · 被引用次数：222 · 研究领域：Pulmonary Hypertension Research and Treatments、Inflammasome and immune disorders、Frequency Control in Power Systems

Abstract Rationale Pulmonary arterial hypertension (PAH) often results in death from right ventricular failure (RVF). NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3)-macrophage activation may promote RVF in PAH. Objectives Evaluating the contribution of the NLRP3 inflammasome in RV macrophages to PAH RVF. Methods Rats with decompensated RV hypertrophy (monocrotaline [MCT] and Sugen-5416 hypoxia [SuHx]) were compared with compensated RV hypertrophy rats (pulmonary artery banding). Echocardiography and right heart catheterization were performed. Macrophages, atrial natriuretic peptides, and fibrosis were evaluated by microscopy or flow cytometry. NLRP3 inflammasome activation and cardiotoxicity were confirmed by immunoblot and in vitro strategies. MCT rats were treated with SC-144 (a GP130 antagonist) or MCC950 (an NLRP3 inhibitor). Macrophage–NLRP3 activity was evaluated in patients with PAH RVF. Measurements and Main Results Macrophages, fibrosis, and atrial natriuretic peptides were increased in MCT and SuHx RVs but not in left ventricles or pulmonary artery banding rats. Although MCT RV macrophages were inflammatory, lung macrophages were antiinflammatory. CCR2+ macrophages (monocyte-derived) were increased in MCT and SuHx RVs and highly expressed NLRP3. The macrophage–NLRP3 pathway was upregulated in patients with PAH with decompensated RVs. Cultured MCT monocytes showed NLRP3 activation, and in coculture experiments resulted in...