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

Ruaa Al-Qazazi, Patricia D.A. Lima, Sasha Z. Prisco, Francois Potus, Asish Dasgupta, Kuang Hueih Chen, Lian Tian, Rachel E.T. Bentley, Jeff Mewburn, Ashley Y. Martin, Danchen Wu, Oliver Jones, Donald H. Maurice, Sebastien Bonnet, Steeve Provencher, Kurt W. Prins, Stephen L. Archer

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

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 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 (signal transducer and activator of transcription 3) activation, and improved RV function without regressing pulmonary vascular disease. Conclusions: NLRP3–macrophage activation occurs in the decompensated RV in preclinical PAH models and patients with PAH. Inhibiting GP130 or NLRP3 signaling improves RV function. The concept that PAH RVF results from RV inflammation rather than solely from elevated RV afterload suggests a new therapeutic paradigm.

Original languageEnglish (US)
Pages (from-to)608-624
Number of pages17
JournalAmerican journal of respiratory and critical care medicine
Volume206
Issue number5
DOIs
StatePublished - Sep 1 2022

Bibliographical note

Funding Information:
Supported by the NIH grants NIH R01HL113003 and NIH R01HL071115 (S.L.A.); Canada Foundation for Innovation 229252 and 33012 (S.L.A.); Tier 1 Canada Research Chair in Mitochondrial Dynamics and Translational Medicine 950-229252 (S.L.A.); and the William J. Henderson Foundation (S.L.A.); The William M. Spear Endowment Fund in Pulmonary Research (Health Sciences Internal Grant Competition 2019) (NIH UL1TR002494 [D.H.M. and P.D.A.L.); Pulmonary Hypertension Association of Canada (The Mohammed Family PH research Scholarship) (R.A.-Q.); The University of Minnesota Clinical and Translational Science Award (NIH UL1 TR002494 [S.Z.P.]); The University of Minnesota Faculty Research Development Grant, National Institutes of Health (NIH) (NIH F32 HL154533, NIH T32 HL144472 [S.Z.P.]); Minnesota Medical School Academic Investment Educational Program Grant (NIH K08 HL140100 [K.W.P.]); Cardiovascular Medical Research and Education Fund; United Therapeutics Jenesis Award; Lillehei Heart Institute Cardiovascular Seed Grant.

Publisher Copyright:
Copyright © 2022 by the American Thoracic Society.

Keywords

  • CCR2
  • IL-1β
  • MCC950
  • SC-144
  • mitochondrial fission

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