Host PGD2 acting on DP2 receptor attenuates Schistosoma mansoni infection-driven hepatic granulomatous fibrosis

Abstract

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 D2 (PGD2) as a potential pro-fibrotic candidate in schistosomal context, although corroboratory in vivo evidence is still lacking. Here, to investigate the role of PGD2 and its cognate receptor DP2 in vivo, impairment of PGD2 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 PGD2 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-{beta} and IL-13 in infected animals. LTC4, one of the 5-lipoxygenase products described as potential anti-fibrotic mediators in the schistosomal liver, was reduced after HQL-79 and CAY10471 treatments. Moreover, LTC4 tissue levels were inversely correlated with collagen production in granulomatous livers. An ample body of data supports the role of S. mansoni-driven DP2-mediated activation of eosinophils as a key down-regulator of schistosomiasis-induced liver fibrosis, including: (i) HQL-79 and CAY10471 impaired systemic eosinophilia, drastically decreasing eosinophils within peritoneum and hepatic granulomas of infected animals; (ii) peritoneal eosinophils were identified as the only cells producing LTC4 in PGD2-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 LTC4 in vitro in a PGD2/DP2 dependent manner. So, our findings uncover that PGD2 by activating DP2 receptors stimulates cysLTs production by eosinophils, while 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 PGD2/DP2 in schistosomiasis. Author summaryAccumulation of scar tissue (fibrosis)in the liver is the main cause of health problems associated with schistosomiasis even after the parasite is eliminated by treatment with anthelmintics. Previous experiments with isolated cells in culture have identified a potential role for a lipid mediator, PGD2, in promoting liver fibrosis leading to suggestions that PGD2 inhibition may be beneficial for the people infected with Schistosoma parasite. However, there was no direct evidence in an infection model to support these claims. Here, we described the effect of inhibiting the production or action of PGD2 in a mouse model of schistosomiasis. We identified the cell target and mechanism of action of PGD2s participation in schistosomiasis. However, our data indicates that PGD2 protects the liver from fibrosis. Thus, inhibition of PGD2 action in patients infected with the Schistosoma parasite may aggravate the condition and promote faster liver failure and should not be pursued as a treatment option.