Inhibition of sphingosine 1-phosphate receptor 3 ameliorates bleomycin-induced pulmonary fibrosis by suppressing macrophage M2 polarization  

作　　者：Huijun Qiu Jiang Liu Jingyi You Ou Zhou Chang Hao Yi Shu Deyu Ma Wenjing Zou Linghuan Zhang Enmei Liu Zhengxiu Luo Luo Ren Gang Geng Lin Zou Danyi Peng Zhou Fu 

机构地区：[1]Department of Respiratory Medicine,Children’s Hospital of Chongqing Medical University,National Clinical Research Center for Child Health and Disorders,Ministry of Education Key Laboratory of Child Development and Disorders,Chongqing Key Laboratory of Pediatrics,Chongqing 400014,China [2]Department of Neonatology,Children’s Hospital of Chongqing Medical University,Chongqing 400014,China [3]Department of Otolaryngology,Children’s Hospital of Chongqing Medical University,Chongqing 400014,China [4]Center of Clinical Molecular Medicine,Children’s Hospital of Chongqing Medical University,Chongqing 400014,China [5]Clinical Research Unit,Institute of Pediatric Infection,Immunity and Critical Care Medicine,Children’s Hospital of Shanghai Jiaotong University Medical School,Shanghai 200062,China

出　　处：《Genes & Diseases》2025年第3期508-522,共15页基因与疾病(英文)

基　　金：supported by the General Basic Research Project from the Ministry of Education Key Laboratory of Child Development and Disorders(China)(No.GBRP202115);the Chongqing Science and Technology Bureau Major Project(China)(No.cstc2020jcyj-msxmX0782).

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 moleculesphingosine-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 miceand specific overexpression of S1pr3 in the infiltrated M2 macrophages. We constructed LysM-Cre^(+)/S1pr3^(flox/flox) mice, in which S1pr3 was conditionally depleted in myeloid cells, andthis depletion protected mice from bleomycin-induced lung injury and fibrosis, with reducedM2 macrophage accumulation in the lung. Increased S1pr3 expression was found in bonemarrow-derived macrophages after alternatively activated by IL4 ex vivo, while loss ofS1pr3 attenuated IL-4-induced M2 polarization in bone marrow-derived macrophages by repressing the PI3K/Akt-Stat3 signaling pathway. Moreover, the S1pr3 inhibitors CAY10444 andTY52156 exerted protective effects on pulmonary fibrosis in mice. Taken together, ourresearch showed that inhibition of S1pr3 ameliorates bleomycin-induced pulmonary fibrosisby reducing macrophage M2 polarization via the PI3K/Akt-Stat3 signaling pathway, indicatingthat S1pr3 may be a potential target for pulmonary fibrosis treatment.

关 键 词：BLEOMYCIN IL-4 M2 polarization MACROPHAGE Pulmonary fibrosis S1pr3 

分 类 号：R563[医药卫生—呼吸系统]