Elevation of pulmonary CD163+ and CD204+ macrophages is associated with the clinical course of idiopathic pulmonary fibrosis patients

Takashi Nouno, Masaki Okamoto, Koji Ohnishi, Shinjiro Kaieda, Masaki Tominaga, Yoshiaki Zaizen, Masao Ichiki, Seiya Momosaki, Masayuki Nakamura, Kiminori Fujimoto, Junya Fukuoka, Shigeki Shimizu, Yoshihiro Komohara, Tomoaki Hoshino

Abstract

Background: M2-like/repair macrophages are thought to contribute to fibrotic process of idiopathic pulmonary fibrosis (IPF). We analyzed the association between pulmonary accumulation of M2-like macrophages and survival in IPF patients.
Methods: Lung tissues were obtained by surgical lung biopsy from patients with IPF (n=16), nonspecific interstitial pneumonia (NSIP, n=8) and control subjects (n=14). Samples were also obtained at autopsy from 9 patients who died of acute exacerbation (AE) of IPF. Lung specimens and/or human peripheral blood mononuclear cells-derived macrophages were evaluated by immunohistochemistry for expression of CD68 (pan-macrophage marker), CD163, and CD204 (M2-like macrophage markers), and by in situ mRNA hybridization and ELISA for production of transforming growth factor-β1 (TGF-β1).
Results: CD68+, CD163+, and CD204+ cell counts and CD163+/CD68+ and CD204+/CD68+ cell ratios were comparable in IPF and NSIP lung tissues and significantly higher than in control tissues. IPF-AE lung samples contained significantly elevated CD68+ and CD163+ cell counts and CD163+/CD68+ cell ratio compared with IPF samples, whereas CD204+ cell counts and CD204+/CD68+ cells ratio did not differ. High CD163+/CD68+ and CD204+/CD68+ cell ratios were significantly associated with shorter overall survival and time-to-AE in IPF patients. In vitro-differentiated human CD163+ and CD204+ macrophages both secreted TGF-β1; however, the novel IPF drug pentraxin 2/serum amyloid protein could suppress secretion only by CD204+ macrophages.
Conclusions: Pulmonary accumulation of CD163+ and CD204+ macrophages is associated with worse clinical course in IPF patients. Suppression of macrophage activation and TGF-β1 secretion may be a potential therapeutic target for IPF.