博莱霉素
1-磷酸鞘氨醇
巨噬细胞极化
肺纤维化
磷酸盐
S1PR1型
纤维化
化学
受体
鞘氨醇
巨噬细胞
医学
药理学
癌症研究
内科学
生物化学
化疗
血管内皮生长因子
血管内皮生长因子A
体外
血管内皮生长因子受体
作者
Huijun Qiu,Jiang Liu,Jingyi You,Zhou Ou,Chang Hao,Yi Shu,De-Yu Ma,Wenjing Zou,Linghuan Zhang,Haibo Liu,Zhengxiu Luo,Ren Luo,Gang Geng,Lin Zou,Dan-Yi Peng,Zhou Fu
标识
DOI:10.1016/j.gendis.2024.101244
摘要
Pulmonary fibrosis is a devastating lung disease without effective treatment options. Sphingosine-1-phosphate receptor 3 (S1pr3), a receptor for the lipid signaling molecule sphingosine-1-phosphate, has been shown to mediate the development of pulmonary fibrosis, although the underlying mechanism is not fully understood. Here, we found increased expression of S1pr3 in the lung during the process of bleomycin-induced pulmonary fibrosis in mice and specific overexpression of S1pr3 in the infiltrated M2 macrophages. We constructed LysM-Cre+/S1pr3flox/flox mice, in which S1pr3 was conditionally depleted in myeloid cells, and this depletion protected mice from bleomycin-induced lung injury and fibrosis, with reduced M2 macrophage accumulation in the lung. Increased S1pr3 expression was found in bone marrow-derived macrophages after alternatively activated by IL4 ex vivo, while loss of S1pr3 attenuated IL-4-induced M2 polarization in bone marrow-derived macrophages by repressing the PI3K/Akt-Stat3 signaling pathway. Moreover, the S1pr3 inhibitors CAY10444 and TY52156 exerted protective effects on pulmonary fibrosis in mice. Taken together, our research showed that inhibition of S1pr3 ameliorates bleomycin-induced pulmonary fibrosis by reducing macrophage M2 polarization via the PI3K/Akt-Stat3 signaling pathway, indicating that S1pr3 may be a potential target for pulmonary fibrosis treatment.
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