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 m...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.展开更多
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).
文摘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.
