A p53-TLR3 axis ameliorates pulmonary hypertension by inducing BMPR2 via IRF3

• Published in: iScience Vol. 26; no. 2; p. 105935
• Main Authors: Bhagwani, Aneel R., Ali, Mehboob, Piper, Bryce, Liu, Mingjun, Hudson, Jaylen, Kelly, Neil, Bogamuwa, Srimathi, Yang, Hu, Londino, James D., Bednash, Joseph S., Farkas, Daniela, Mallampalli, Rama K., Nicolls, Mark R., Ryan, John J., Thompson, A.A. Roger, Chan, Stephen Y., Gomez, Delphine, Goncharova, Elena A., Farkas, Laszlo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.02.2023; Elsevier
• Subjects: Biological sciences; Cell biology; Molecular biology; Cell biology; Molecular biology; Biological sciences
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2023.105935

Pulmonary arterial hypertension (PAH) features pathogenic and abnormal endothelial cells (ECs), and one potential origin is clonal selection. We studied the role of p53 and toll-like receptor 3 (TLR3) in clonal expansion and pulmonary hypertension (PH) via regulation of bone morphogenetic protein (BMPR2) signaling. ECs of PAH patients had reduced p53 expression. EC-specific p53 knockout exaggerated PH, and clonal expansion reduced p53 and TLR3 expression in rat lung CD117+ ECs. Reduced p53 degradation (Nutlin 3a) abolished clonal EC expansion, induced TLR3 and BMPR2, and ameliorated PH. Polyinosinic/polycytidylic acid [Poly(I:C)] increased BMPR2 signaling in ECs via enhanced binding of interferon regulatory factor-3 (IRF3) to the BMPR2 promoter and reduced PH in p53−/− mice but not in mice with impaired TLR3 downstream signaling. Our data show that a p53/TLR3/IRF3 axis regulates BMPR2 expression and signaling in ECs. This link can be exploited for therapy of PH. [Display omitted] •Clonal expansion yields p53- and TLR3-deficient endothelial cells•The TLR3 ligand Poly(I:C) promotes BMPR2 expression endothelial cells•Poly(I:C) increases binding of IRF3 to the BMPR2 promoter•Poly(I:C) reduces pulmonary hypertension in p53−/−, but not in TRIFLPS2 mice Biological sciences; Molecular biology; Cell biology