| Author | Ferreira, Giovanna Nogueira Pezzella | |
| Author | Pão, Camila Ribeiro Rodrigues de | |
| Author | Bellas, Isaac | |
| Author | Silva, Tatiana Luna Gomes da | |
| Author | Muniz, Valdirene de Souza | |
| Author | Paiva, Ligia de Almeida | |
| Author | Amorim, Natália Recardo Tasmo de | |
| Author | Canetti, Claudio de Azevedo | |
| Author | Bozza, Patricia Torres | |
| Author | Diaz, Bruno Lourenço | |
| Author | Melo, Christianne Bandeira de | |
| Access date | 2024-10-24T13:31:43Z | |
| Available date | 2024-10-24T13:31:43Z | |
| Document date | 2024 | |
| Citation | FERREIRA, Giovanna Nogueira Pezzella et al. Endogenous PGD₂ acting on DP2 receptor counter regulates Schistosoma mansoni infection-driven hepatic granulomatous fibrosis. PLoS Pathogens, v. 20, n. 8, p. 1-24, 22 Aug. 2024. | |
| ISSN | 1553-7366 | |
| URI | https://www.arca.fiocruz.br/handle/icict/66710 | |
| Description | Author summary: Accumulation 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 PGD₂'s 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. | en_US |
| Description | Produção científica do Laboratório de Imunofarmacologia. | pt_BR |
| Sponsorship | This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brazil, grant 310475/2017-1 and 406019/2021-5 to Christianne Bandeira de Melo); Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (grants E-26/202.926/2015 and E26/302.534/2019 to Christianne Bandeira de Melo; E-26/203.013/2018 and E-26/201.189/2022 to Bruno Lourenço Diaz); and by fellowships from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (to Tatiana Luna Gomes da Silva and Natália Recardo Tasmo de Amorim) and Conselho Nacional de Desenvolvimento Científico e Tecnológico to Giovanna Nogueira Pezzella Ferreira. | |
| Language | eng | en_US |
| Publisher | Public Library of Science | |
| Rights | open access | |
| Title | Endogenous PGD₂ acting on DP2 receptor counter regulates Schistosoma mansoni infection-driven hepatic granulomatous fibrosis | en_US |
| Type | Article | |
| DOI | 10.1371/journal.ppat.1011812 | |
| 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-β and IL-13 in infected animals. In contrast, infection-induced enhanced LTC₄ synthesis in the schistosomal liver was reduced after HQL-79 and CAY10471 treatments, and therefore, inversely correlated with collagen production in granulomatous livers. Like PGD₂-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 LTC₄ 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 LTC₄ 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 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 granulomatous stellate cells-derived PGD₂ 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 PGD₂/DP2 in schistosomiasis. | en_US |
| Affilliation | Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Biofísica Carlos Chagas Filho. Programa Temático de Imunobiologia. Laboratório de Inflamação. Rio de Janeiro, RJ, Brasil. | |
| Affilliation | Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Biofísica Carlos Chagas Filho. Programa Temático de Imunobiologia. Laboratório de Inflamação. Rio de Janeiro, RJ, Brasil. | |
| Affilliation | Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Biofísica Carlos Chagas Filho. Programa Temático de Imunobiologia. Laboratório de Inflamação. Rio de Janeiro, RJ, Brasil. | |
| Affilliation | Universidade do Estado do Rio de Janeiro. Centro de Educação e Humanidades. Departamento de Ciências da Natureza. Rio de Janeiro, RJ, Brasil. | |
| Affilliation | Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Ciências Biomédicas. Laboratório de Farmacologia da Dor e da Inflamação. Rio de Janeiro, RJ, Brasil. | |
| Affilliation | Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Ciências Biomédicas. Laboratório de Farmacologia da Dor e da Inflamação. Rio de Janeiro, RJ, Brasil. | |
| Affilliation | Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Biofísica Carlos Chagas Filho. Programa Temático de Imunobiologia. Laboratório de Inflamação. Rio de Janeiro, RJ, Brasil. | |
| Affilliation | Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Biofísica Carlos Chagas Filho. Programa Temático de Imunobiologia. Laboratório de Inflamação. Rio de Janeiro, RJ, Brasil. | |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil. | |
| Affilliation | Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Biofísica Carlos Chagas Filho. Programa Temático de Imunobiologia. Laboratório de Inflamação. Rio de Janeiro, RJ, Brasil. | |
| Affilliation | Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Biofísica Carlos Chagas Filho. Programa Temático de Imunobiologia. Laboratório de Inflamação. Rio de Janeiro, RJ, Brasil. | |
| Subject | Eosinophils | en_US |
| Subject | Schistosoma mansoni | en_US |
| Subject | Granulomas | en_US |
| Subject | Fibrosis | en_US |
| Subject | Parasitic diseases | en_US |
| Subject | Eggs | en_US |
| Subject | Eosinophilia | en_US |
| Subject | Lipids | en_US |
| e-ISSN | 1553-7374 | |
| xmlui.metadata.dc.subject.ods | 03 Saúde e Bem-Estar | |
| xmlui.metadata.dc.subject.ods | 06 Água potável e saneamento | |
| xmlui.metadata.dc.subject.ods | 09 Indústria, inovação e infraestrutura | |
| xmlui.metadata.dc.subject.ods | 17 Parcerias e meios de implementação | |
