Prostaglandin I2 (PGI(2)) inhibits Brucella abortus internalization in macrophages via PGI(2) receptor signaling, and its analogue affects immune response and disease outcome in mice

Abstract

To date, the implications of prostaglandin I2 (PGI(2)), a prominent lipid mediator for modulation of immune responses, has not been clearly understood in Brucella infection. In this study, we found that cyclooxygenase-2 (COX-2) was significantly expressed in both infected bone marrow-derived macrophages (BMMs) and RAW 264.7 cells. Prostaglandin I2 synthase (PTGIS) expression was not significantly changed, and PGI(2) receptor (PTGIR) expression was downregulated in BMMs but upregulated in RAW 264.7 macrophages at late infection. Here, we presented that PGI(2), a COX-derived metabolite, was produced by macrophages during Brucella infection and its production was regulated by COX-2 and IL-10. We suggested that PGI(2) and selexipag, a potent PGI(2) analogue, inhibited Brucella internalization through IP signaling which led to down-regulation of F-actin polymerization and p38 alpha MAPK activity. Administration with selexipag suppressed immune responses and resulted in a notable reduction in bacterial burden in spleen of Brucella-challenged mice. Taken together, our study is the first to characterize PGI(2) synthesis and its effect in evasion strategy of macrophages against Brucella infection.