Macrophage-NLRP3 activation promotes right ventricle failure in pulmonary arterial hypertension

Al-Qazazi, Ruaa and Lima, Patricia D.A. and Prisco, Sasha Z. and Potus, Francois and Dasgupta, Asish and Chen, Kuang-Hueih and Tian, Lian and Bentley, Rachel E. T. and Mewburn, Jeff and Martin, Ashley Y. and Wu, Danchen and Jones, Oliver and Maurice, Donald H. and Bonnet, Sebastien and Provencher, Steeve and Prins, Kurt W. and Archer, Stephen L. (2022) Macrophage-NLRP3 activation promotes right ventricle failure in pulmonary arterial hypertension. American Journal of Respiratory and Critical Care Medicine. ISSN 1535-4970 (https://doi.org/10.1164/rccm.202110-2274OC)

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Abstract

Rationale: Pulmonary arterial hypertension (PAH) often results in death from right ventricular failure (RVF). NLRP3-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 (RVH) [monocrotaline (MCT) and Sugen-5416 hypoxia (SuHx)] were compared with compensated RVH rats [pulmonary artery banding (PAB)]. Echocardiography and right heart catheterization were performed. Macrophages, atrial natriuretic peptide (ANP) 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) and MCC950 (an NLRP3 inhibitor). Macrophage-NLRP3 activity was evaluated in PAH-RVF patients. Measurements and Main Results: Macrophages, fibrosis, and ANP were increased in MCT and SuHx-RVs but not LVs or PAB rats. While MCT-RV macrophages were inflammatory, lung macrophages were anti-inflammatory. CCR2+ macrophages (monocyte-derived) were increased in MCT- and SuHx-RVs and highly expressed NLRP3. The macrophage-NLRP3 pathway was upregulated in PAH patients’ decompensated RVs. Cultured MCT-monocytes showed NLRP3 activation, and in co-culture experiments resulted in cardiomyocyte mitochondrial damage, which MCC950 prevented. In vivo, MCC950 reduced NLRP3 activation and regressed pulmonary vascular disease and RVF. SC-144 reduced RV-macrophages and NLRP3 content, prevented STAT3 activation, and improved RV function without regressing pulmonary vascular disease. Conclusion: NLRP3-macrophage activation occurs in the decompensated RV in preclinical PAH models and PAH patients. Inhibiting GP130 or NLRP3 signaling improves RV function. The concept that PAH-RVF results from RV inflammation rather than solely from elevated RV afterload suggest a new therapeutic paradigm.

ORCID iDs

Al-Qazazi, Ruaa, Lima, Patricia D.A., Prisco, Sasha Z., Potus, Francois, Dasgupta, Asish, Chen, Kuang-Hueih, Tian, Lian ORCID logoORCID: https://orcid.org/0000-0002-9699-8009, Bentley, Rachel E. T., Mewburn, Jeff, Martin, Ashley Y., Wu, Danchen, Jones, Oliver, Maurice, Donald H., Bonnet, Sebastien, Provencher, Steeve, Prins, Kurt W. and Archer, Stephen L.;