Idiopathic pulmonary fibrosis is a devastating disease with poor prognosis. The pathogenic role of the
lysophospholipid mediator
sphingosine-1-phosphate and its receptor S1PR2 in lung
fibrosis is unknown. We show here that genetic deletion of S1pr2 strikingly attenuated lung
fibrosis induced by repeated
injections of
bleomycin in mice. We observed by using S1pr2LacZ/+ mice that S1PR2 was expressed in alveolar macrophages, vascular endothelial cells and alveolar epithelial cells in the lung and that S1PR2-expressing cells accumulated in the fibrotic legions. Bone marrow chimera experiments suggested that S1PR2 in bone marrow-derived cells contributes to the development of lung
fibrosis. Depletion of macrophages greatly attenuated lung
fibrosis.
Bleomycin administration stimulated the
mRNA expression of the profibrotic
cytokines IL-13 and
IL-4 and the M2 markers including
arginase 1, Fizz1/Retnla, Ccl17 and Ccl24 in cells collected from broncho-alveolar lavage fluids (BALF), and S1pr2 deletion markedly diminished the stimulated expression of these genes. BALF cells from
bleomycin-administered wild-type mice showed a marked increase in phosphorylation of STAT6, a
transcription factor which is activated downstream of
IL-13, compared with saline-administered wild-type mice. Interestingly,
in bleomycin-administered S1pr2-/- mice, STAT6 phosphorylation in BALF cells was substantially diminished compared with wild-type mice. Finally, pharmacological S1PR2 blockade in S1pr2+/+ mice alleviated
bleomycin-induced lung
fibrosis. Thus, S1PR2 facilitates lung
fibrosis through the mechanisms involving augmentation of
IL-13 expression and its signaling in BALF cells, and represents a novel target for treating lung
fibrosis.