Role of Interleukin 34 in Pulmonary Vascular Remodeling Associated With Fibrosing Interstitial Lung Disease
Tetsuro Yokokawa, Shota Ueda, Kazuto Nishiura, Satoshi Okochi, Ryo Ogawara, Takatoyo Kiko, Shunsuke Miura, Tomofumi Misaka, Masayoshi Oikawa, Yusuke Masuishi, Takeyasu Kakamu, Yoshinori Tanino, Yoko Shibata, Yuko Hashimoto, Satoshi Muto, Hiroyuki Suzuki, Ken‐ichi Inoue, Kazuhiko Ikeda, Kazuhiko Nakazato, Takafumi Ishida, Yasuchika TakeishiABSTRACT
Pulmonary hypertension with fibrosing interstitial lung disease is characterized by progressive pulmonary vascular remodeling and poor prognosis. Although inflammation and macrophage activation contribute to vascular remodeling, upstream mediators remain incompletely defined. Interleukin 34 (IL34), a ligand of colony‐stimulating factor‐1 receptor, regulates macrophage differentiation and recruitment. The objective is to elucidate the role of IL34 in pulmonary vascular remodeling associated with fibrosing interstitial lung disease. We investigated human lung samples, in vitro studies, using a murine model of pulmonary hypertension with fibrosing interstitial lung disease, and smooth muscle cell‐specific IL34‐deficient mice. IL34 expression was increased in the pulmonary arteries of patients with fibrosing interstitial lung disease with pulmonary vascular remodeling. IL34 was upregulated in pulmonary artery smooth muscle cells in a murine model of pulmonary hypertension with fibrosing interstitial lung disease, promoting osteopontin production in macrophages. Smooth muscle cell‐specific IL34 deficiency attenuated right ventricular systolic pressure, right ventricular hypertrophy, vascular remodeling, and perivascular macrophage accumulation in a murine model of pulmonary hypertension with fibrosing interstitial lung disease. Osteopontin from IL34‐induced macrophages promoted pulmonary artery smooth muscle cell proliferation. These findings identify smooth muscle cell‐derived IL34 as a contributor to pulmonary vascular remodeling associated with fibrosing interstitial lung disease.