Jason D Coombes, Paul P Manka, Marzena Swiderska-Syn, Danielle T Vannan, Antonio Riva, Lee C Claridge, Cynthia Moylan, Ayako Suzuki, Marco A Briones-Orta, Rasha Younis, Naoto Kitamura, Svenja Sydor, Shanna Bittencourt, Zhiyong Mi, Paul C Kuo, Anna Mae Diehl, Leo A van Grunsven, Shilpa Chokshi, Ali Canbay, Manal F Abdelmalek, Patricia Aspichueta, Salvatore Papa, Bertus Eksteen, Wing-Kin Syn
{"title":"骨蛋白促进胆管细胞分泌趋化因子，支持 MASH 中巨噬细胞的招募和纤维化。","authors":"Jason D Coombes, Paul P Manka, Marzena Swiderska-Syn, Danielle T Vannan, Antonio Riva, Lee C Claridge, Cynthia Moylan, Ayako Suzuki, Marco A Briones-Orta, Rasha Younis, Naoto Kitamura, Svenja Sydor, Shanna Bittencourt, Zhiyong Mi, Paul C Kuo, Anna Mae Diehl, Leo A van Grunsven, Shilpa Chokshi, Ali Canbay, Manal F Abdelmalek, Patricia Aspichueta, Salvatore Papa, Bertus Eksteen, Wing-Kin Syn","doi":"10.1111/liv.16131","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and aims: </strong>Osteopontin (OPN) promotes the ductular reaction and is a major driver of chronic liver disease (CLD) progression. Although CLD is characterised by the accumulation of inflammatory cells including macrophages around the peri-portal regions, the influence of OPN on recruitment is unclear. We investigated the role of OPN in cholangiocyte chemokine production and macrophage recruitment by combining in vivo, in vitro, and in silico approaches.</p><p><strong>Methods: </strong>The effects of OPN on cholangiocyte chemokine production and macrophage migration were assessed in culture, alongside RNA-sequencing to identify genes and pathways affected by OPN depletion. Murine liver injury models were used to assess liver chemokine expression and liver macrophage/monocyte recruitment. OPN and chemokine expression were analysed in liver tissue and plasma from biopsy-proven metabolic dysfunction-associated alcoholic steatohepatitis (MASH) patients.</p><p><strong>Results: </strong>OPN-knockdown in cholangiocytes reduced chemokine secretion. RNA-sequencing showed OPN-related effects clustered around immunity, chemotaxis and chemokine production. Macrophage exposure to cholangiocyte-conditioned media showed OPN-supported migration via chemokines chemokine (C-C motif) ligand (CCL)2, CCL5 and chemokine (C-X-C motif) ligand (CXCL)1. These effects were related to NF-κB signalling. Murine liver fibrosis was accompanied by upregulated liver OPN, CCL2, CCL5 and CXCL1 mRNA, and accumulation of liver cluster of differentiation (CD)11b/F4/80<sup>+</sup>CC chemokine receptors (CCR2)<sup>high</sup> macrophages but treatment with OPN-specific neutralising aptamers reduced fibrosis, chemokine mRNAs and accumulation of liver CD11b/F4/80<sup>+</sup>CCR2<sup>high</sup>/lymphocyte antigen 6 complex<sup>high</sup> inflammatory monocytes. In human MASH, liver OPN correlated with chemokines CCL2 and IL8 in association with portal injury and fibrosis. Plasma OPN, serum CCL2 and IL8 also increased with fibrosis stage.</p><p><strong>Conclusions: </strong>OPN promotes cholangiocyte chemokine secretion and the accumulation of pro-inflammatory monocytes. These data support neutralisation of OPN as an anti-inflammatory and anti-fibrotic strategy.</p>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":" ","pages":""},"PeriodicalIF":6.0000,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Osteopontin Promotes Cholangiocyte Secretion of Chemokines to Support Macrophage Recruitment and Fibrosis in MASH.\",\"authors\":\"Jason D Coombes, Paul P Manka, Marzena Swiderska-Syn, Danielle T Vannan, Antonio Riva, Lee C Claridge, Cynthia Moylan, Ayako Suzuki, Marco A Briones-Orta, Rasha Younis, Naoto Kitamura, Svenja Sydor, Shanna Bittencourt, Zhiyong Mi, Paul C Kuo, Anna Mae Diehl, Leo A van Grunsven, Shilpa Chokshi, Ali Canbay, Manal F Abdelmalek, Patricia Aspichueta, Salvatore Papa, Bertus Eksteen, Wing-Kin Syn\",\"doi\":\"10.1111/liv.16131\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and aims: </strong>Osteopontin (OPN) promotes the ductular reaction and is a major driver of chronic liver disease (CLD) progression. Although CLD is characterised by the accumulation of inflammatory cells including macrophages around the peri-portal regions, the influence of OPN on recruitment is unclear. We investigated the role of OPN in cholangiocyte chemokine production and macrophage recruitment by combining in vivo, in vitro, and in silico approaches.</p><p><strong>Methods: </strong>The effects of OPN on cholangiocyte chemokine production and macrophage migration were assessed in culture, alongside RNA-sequencing to identify genes and pathways affected by OPN depletion. Murine liver injury models were used to assess liver chemokine expression and liver macrophage/monocyte recruitment. OPN and chemokine expression were analysed in liver tissue and plasma from biopsy-proven metabolic dysfunction-associated alcoholic steatohepatitis (MASH) patients.</p><p><strong>Results: </strong>OPN-knockdown in cholangiocytes reduced chemokine secretion. RNA-sequencing showed OPN-related effects clustered around immunity, chemotaxis and chemokine production. Macrophage exposure to cholangiocyte-conditioned media showed OPN-supported migration via chemokines chemokine (C-C motif) ligand (CCL)2, CCL5 and chemokine (C-X-C motif) ligand (CXCL)1. These effects were related to NF-κB signalling. Murine liver fibrosis was accompanied by upregulated liver OPN, CCL2, CCL5 and CXCL1 mRNA, and accumulation of liver cluster of differentiation (CD)11b/F4/80<sup>+</sup>CC chemokine receptors (CCR2)<sup>high</sup> macrophages but treatment with OPN-specific neutralising aptamers reduced fibrosis, chemokine mRNAs and accumulation of liver CD11b/F4/80<sup>+</sup>CCR2<sup>high</sup>/lymphocyte antigen 6 complex<sup>high</sup> inflammatory monocytes. In human MASH, liver OPN correlated with chemokines CCL2 and IL8 in association with portal injury and fibrosis. Plasma OPN, serum CCL2 and IL8 also increased with fibrosis stage.</p><p><strong>Conclusions: </strong>OPN promotes cholangiocyte chemokine secretion and the accumulation of pro-inflammatory monocytes. These data support neutralisation of OPN as an anti-inflammatory and anti-fibrotic strategy.</p>\",\"PeriodicalId\":18101,\"journal\":{\"name\":\"Liver International\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":6.0000,\"publicationDate\":\"2024-10-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Liver International\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1111/liv.16131\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"GASTROENTEROLOGY & HEPATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Liver International","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/liv.16131","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
Osteopontin Promotes Cholangiocyte Secretion of Chemokines to Support Macrophage Recruitment and Fibrosis in MASH.
Background and aims: Osteopontin (OPN) promotes the ductular reaction and is a major driver of chronic liver disease (CLD) progression. Although CLD is characterised by the accumulation of inflammatory cells including macrophages around the peri-portal regions, the influence of OPN on recruitment is unclear. We investigated the role of OPN in cholangiocyte chemokine production and macrophage recruitment by combining in vivo, in vitro, and in silico approaches.
Methods: The effects of OPN on cholangiocyte chemokine production and macrophage migration were assessed in culture, alongside RNA-sequencing to identify genes and pathways affected by OPN depletion. Murine liver injury models were used to assess liver chemokine expression and liver macrophage/monocyte recruitment. OPN and chemokine expression were analysed in liver tissue and plasma from biopsy-proven metabolic dysfunction-associated alcoholic steatohepatitis (MASH) patients.
Results: OPN-knockdown in cholangiocytes reduced chemokine secretion. RNA-sequencing showed OPN-related effects clustered around immunity, chemotaxis and chemokine production. Macrophage exposure to cholangiocyte-conditioned media showed OPN-supported migration via chemokines chemokine (C-C motif) ligand (CCL)2, CCL5 and chemokine (C-X-C motif) ligand (CXCL)1. These effects were related to NF-κB signalling. Murine liver fibrosis was accompanied by upregulated liver OPN, CCL2, CCL5 and CXCL1 mRNA, and accumulation of liver cluster of differentiation (CD)11b/F4/80+CC chemokine receptors (CCR2)high macrophages but treatment with OPN-specific neutralising aptamers reduced fibrosis, chemokine mRNAs and accumulation of liver CD11b/F4/80+CCR2high/lymphocyte antigen 6 complexhigh inflammatory monocytes. In human MASH, liver OPN correlated with chemokines CCL2 and IL8 in association with portal injury and fibrosis. Plasma OPN, serum CCL2 and IL8 also increased with fibrosis stage.
Conclusions: OPN promotes cholangiocyte chemokine secretion and the accumulation of pro-inflammatory monocytes. These data support neutralisation of OPN as an anti-inflammatory and anti-fibrotic strategy.
期刊介绍：
Liver International promotes all aspects of the science of hepatology from basic research to applied clinical studies. Providing an international forum for the publication of high-quality original research in hepatology, it is an essential resource for everyone working on normal and abnormal structure and function in the liver and its constituent cells, including clinicians and basic scientists involved in the multi-disciplinary field of hepatology. The journal welcomes articles from all fields of hepatology, which may be published as original articles, brief definitive reports, reviews, mini-reviews, images in hepatology and letters to the Editor.
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