Interleukin-6/interleukin-21 signaling axis is critical in the pathogenesis of pulmonary arterial hypertension.
IL-6 is a multifunctional proinflammatory cytokine that is elevated in the serum of patients with pulmonary arterial hypertension (PAH) and can predict the survival of patients with idiopathic PAH (IPAH). Previous animal experiments and clinical human studies indicate that IL-6 is important in PAH; however, the molecular mechanisms of IL-6-mediated pathogenesis of PAH have been elusive. Here we identified IL-21 as a downstream target of IL-6 signaling in PAH. First, we found that IL-6 blockade by the monoclonal anti-IL-6 receptor antibody, MR16-1, ameliorated hypoxia-induced pulmonary hypertension (HPH) and prevented the hypoxia-induced accumulation of Th17 cells and M2 macrophages in the lungs. Consistently, the expression levels of IL-17 and IL-21 genes, one of the signature genes for Th17 cells, were significantly up-regulated after hypoxia exposure in the lungs of mice treated with control antibody but not in the lungs of mice treated with MR16-1. Although IL-17 blockade with an anti-IL-17A neutralizing antibody had no effect on HPH, IL-21 receptor-deficient mice were resistant to HPH and exhibited no significant accumulation of M2 macrophages in the lungs. In accordance with these findings, IL-21 promoted the polarization of primary alveolar macrophages toward the M2 phenotype. Of note, significantly enhanced expressions of IL-21 and M2 macrophage markers were detected in the lungs of IPAH patients who underwent lung transplantation. Collectively, these findings suggest that IL-21 promotes PAH in association with M2 macrophage polarization, downstream of IL-6-signaling. The IL-6/IL-21-signaling axis may be a potential target for treating PAH.
Departments of Cardiovascular Medicine.
Takahiro
T
Hashimoto-Kataoka
Cancer Stem Cell Biology Functional Diagnostic Science.
Naoki
N
Hosen
Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, 565-8565, Japan;
Takashi
T
Sonobe
Departments of Cardiovascular Medicine.
Yoh
Y
Arita
Departments of Cardiovascular Medicine.
Taku
T
Yasui
Departments of Cardiovascular Medicine.
Takeshi
T
Masaki
General Thoracic Surgery.
Masato
M
Minami
Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, 565-8565, Japan;
Tadakatsu
T
Inagaki
Cardiovascular Surgery, and.
Shigeru
S
Miyagawa
Cardiovascular Surgery, and.
Yoshiki
Y
Sawa
Department of Molecular Neuroimmunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0815, Japan;
Masaaki
M
Murakami
Respiratory Medicine, Allergy and Rheumatic Disease, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan;
Atsushi
A
Kumanogoh
Departments of Cardiovascular Medicine.
Keiko
K
Yamauchi-Takihara
General Thoracic Surgery.
Meinoshin
M
Okumura
Laboratory of Immune Regulation, Immunology Frontier Research Center, Osaka University, Suita, Osaka, 565-0871, Japan;
Tadamitsu
T
Kishimoto
Department of Cardiovascular Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, 113-8656, Japan; and Core Research for Evolutional Science and Technology and.
Issei
I
Komuro
Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, 565-8565, Japan;
Mikiyasu
M
Shirai
Departments of Cardiovascular Medicine.
Yasushi
Y
Sakata
Departments of Cardiovascular Medicine, Precursory Research for Embryonic Science and Technology, Japan Science Technology Agency, Kawaguchi, Saitama, 332-0012, Japan ynakaoka@cardiology.med.osaka-u.ac.jp.
Yoshikazu
Y
Nakaoka
D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001794:Blood Pressure; D015153:Blotting, Western; D001837:Body Weights and Measures; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D006801:Humans; D006976:Hypertension, Pulmonary / Q000503:physiopathology*; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism*; D007378:Interleukins / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D053655:Receptors, Interleukin-21 / Q000172:deficiency; D015398:Signal Transduction / Q000502:physiology*; D066253:Vascular Remodeling / Q000502:physiology*; D000098546:Interleukin-21
D000911:Antibodies, Monoclonal; D017931:DNA Primers; D015850:Interleukin-6; D007378:Interleukins; D053655:Receptors, Interleukin-21; D000098546:Interleukin-21
M2 macrophage; Th17 cells; interleukin-21; interleukin-6; pulmonary arterial hypertension