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The primary pathology of hepatic schistosomiasis caused by <jats:italic>Schistosoma japonicum<\/jats:italic> (<jats:italic>S<\/jats:italic>. <jats:italic>japonicum<\/jats:italic>) or <jats:italic>Schistosoma mansoni<\/jats:italic> (<jats:italic>S<\/jats:italic>. <jats:italic>mansoni<\/jats:italic>) infection is egg-induced granuloma and subsequent fibrosis in the liver. Activation of hepatic stellate cells (HSCs) is the central driver of liver fibrosis. Macrophages (M\u03c6), making up 30% of cells in hepatic granulomas, directly or indirectly regulate HSC activation by paracrine mechanisms, via secreting cytokines or chemokines. Currently, M\u03c6-derived extracellular vesicles (EVs) are broadly involved in cell communication with adjacent cell populations. However, whether M\u03c6-derived EVs could target neighboring HSCs to regulate their activation during schistosome infection remains largely unknown. Schistosome egg antigen (SEA) is considered to be the main pathogenic complex mixture involved in liver pathology. Here, we demonstrated that SEA induced M\u03c6 to produce abundant extracellular vesicles, which directly activated HSCs by activating their autocrine TGF-\u03b21 signaling. Mechanistically, EVs derived from SEA-stimulated M\u03c6 contained increased miR-33, which were transferred into HSCs and subsequently upregulated autocrine TGF-\u03b21 in HSCs through targeting and downregulating SOCS3 expression, thereby promoting HSC activation. Finally, we validated that EVs derived from SEA-stimulated M\u03c6 utilized enclosed miR-33 to promote HSC activation and liver fibrosis in <jats:italic>S<\/jats:italic>. <jats:italic>japonicum<\/jats:italic>-infected mice. Overall, our study indicates that M\u03c6-derived EVs play important roles in the paracrine regulation of HSCs during the progression of hepatic schistosomiasis, representing a potential target for the prevention of liver fibrosis in hepatic schistosomiasis.<\/jats:p>","DOI":"10.1371\/journal.pntd.0011385","type":"journal-article","created":{"date-parts":[[2023,5,30]],"date-time":"2023-05-30T17:43:27Z","timestamp":1685468607000},"page":"e0011385","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":10,"title":["Schistosome egg antigen stimulates the secretion of miR-33-carrying extracellular vesicles from macrophages to promote hepatic stellate cell activation and liver fibrosis in schistosomiasis"],"prefix":"10.1371","volume":"17","author":[{"given":"Xin","family":"Qi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanan","family":"Pu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanyan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyang","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongbin","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junling","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jifeng","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yalin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sha","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8271-2428","authenticated-orcid":true,"given":"Chuan","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,5,30]]},"reference":[{"issue":"10163","key":"pntd.0011385.ref001","doi-asserted-by":"crossref","first-page":"2431","DOI":"10.1016\/S0140-6736(18)33008-3","article-title":"Schistosomiasis","volume":"392","author":"R Barnett","year":"2018","journal-title":"Lancet"},{"issue":"11","key":"pntd.0011385.ref002","doi-asserted-by":"crossref","first-page":"e327","DOI":"10.1016\/S1473-3099(22)00221-3","article-title":"Review of 2022 WHO guidelines on the control and elimination of schistosomiasis","volume":"22","author":"NC Lo","year":"2022","journal-title":"Lancet Infect Dis"},{"key":"pntd.0011385.ref003","doi-asserted-by":"crossref","first-page":"2781","DOI":"10.3389\/fimmu.2018.02781","article-title":"Host Regulators of Liver Fibrosis During Human Schistosomiasis.","volume":"9","author":"SD Kamdem","year":"2018","journal-title":"Front Immunol"},{"issue":"12","key":"pntd.0011385.ref004","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/j.pt.2012.09.005","article-title":"Role of resident liver cells in the pathogenesis of schistosomiasis","volume":"28","author":"BJ Anthony","year":"2012","journal-title":"Trends Parasitol"},{"issue":"2","key":"pntd.0011385.ref005","doi-asserted-by":"crossref","first-page":"e12778","DOI":"10.1111\/pim.12778","article-title":"Granuloma formation and tissue pathology in Schistosoma japonicum versus Schistosoma mansoni infections","volume":"43","author":"F Llanwarne","year":"2021","journal-title":"Parasite Immunol"},{"issue":"6","key":"pntd.0011385.ref006","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.pt.2018.02.005","article-title":"Schistosome-Induced Fibrotic Disease: The Role of Hepatic Stellate Cells","volume":"34","author":"JP Carson","year":"2018","journal-title":"Trends Parasitol"},{"issue":"7","key":"pntd.0011385.ref007","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/nrgastro.2017.38","article-title":"Mechanisms of hepatic stellate cell activation","volume":"14","author":"T Tsuchida","year":"2017","journal-title":"Nat Rev Gastroenterol Hepatol"},{"issue":"1","key":"pntd.0011385.ref008","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1002\/jcp.30582","article-title":"Hepatic stellate cells in the injured liver: Perspectives beyond hepatic fibrosis","volume":"237","author":"D. 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