Endogenous PGD2 acting on DP2 receptor counter regulates Schistosoma mansoni infection-driven hepatic granulomatous fibrosis

Identifying new molecular therapies targeted at the severe hepatic fibrosis associated with the granulomatous immune response to Schistosoma mansoni infection is essential to reduce fibrosis-related morbidity/mortality in schistosomiasis. In vitro cell activation studies suggested the lipid molecule prostaglandin D 2 (PGD 2 ) as a potential pro-fibrotic candidate in schistosomal context, although corroboratory in vivo evidence is still lacking. Here, to investigate the role of PGD 2 and its cognate receptor DP2 in vivo , impairment of PGD 2 synthesis by HQL-79 (an inhibitor of the H-PGD synthase) or DP2 receptor inhibition by CAY10471 (a selective DP2 antagonist) were used against the fibrotic response of hepatic eosinophilic granulomas of S . mansoni infection in mice. Although studies have postulated PGD 2 as a fibrogenic molecule, HQL-79 and CAY10471 amplified, rather than attenuated, the fibrotic response within schistosome hepatic granulomas. Both pharmacological strategies increased hepatic deposition of collagen fibers — an unexpected outcome accompanied by further elevation of hepatic levels of the pro-fibrotic cytokines TGF-β and IL-13 in infected animals. In contrast, infection-induced enhanced LTC 4 synthesis in the schistosomal liver was reduced after HQL-79 and CAY10471 treatments, and therefore, inversely correlated with collagen production in granulomatous livers. Like PGD 2 -directed maneuvers, antagonism of cysteinyl leukotriene receptors CysLT1 by MK571 also promoted enhancement of TGF-β and IL-13, indicating a key down-regulatory role for endogenous LTC 4 in schistosomiasis-induced liver fibrosis. An ample body of data supports the role of S . mansoni -driven DP2-mediated activation of eosinophils as the source of LTC 4 during infection, including: (i) HQL-79 and CAY10471 impaired systemic eosinophilia, drastically decreasing eosinophils within peritoneum and hepatic granulomas of infected animals in parallel to a reduction in cysteinyl leukotrienes levels; (ii) peritoneal eosinophils were identified as the only cells producing LTC 4 in PGD 2 -mediated S . mansoni -induced infection; (iii) the magnitude of hepatic granulomatous eosinophilia positively correlates with S . mansoni -elicited hepatic content of cysteinyl leukotrienes, and (iv) isolated eosinophils from S . mansoni -induced hepatic granuloma synthesize LTC 4 in vitro in a PGD 2 /DP2 dependent manner. So, our findings uncover that granulomatous stellate cells-derived PGD 2 by activating DP2 receptors on eosinophils does stimulate production of anti-fibrogenic cysLTs, which endogenously down-regulates the hepatic fibrogenic process of S . mansoni granulomatous reaction — an in vivo protective function which demands caution in the future therapeutic attempts in targeting PGD 2 /DP2 in schistosomiasis.