Pub Date : 2024-01-01DOI: 10.1016/j.jcmgh.2024.01.017
Omar Martinez-Uribe , Thomas C. Becker , Katherine S. Garman
Background & Aims
This review was developed to provide a thorough and effective update on models relevant to esophageal metaplasia, dysplasia, and carcinogenesis, focusing on the advantages and limitations of different models of Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC).
Methods
This expert review was written on the basis of a thorough review of the literature combined with expert interpretation of the state of the field. We emphasized advances over the years 2012–2023 and provided detailed information related to the characterization of established human esophageal cell lines.
Results
New insights have been gained into the pathogenesis of BE and EAC using patient-derived samples and single-cell approaches. Relevant animal models include genetic as well as surgical mouse models and emphasize the development of lesions at the squamocolumnar junction in the mouse stomach. Rat models are generated using surgical approaches that directly connect the small intestine and esophagus. Large animal models have the advantage of including features in human esophagus such as esophageal submucosal glands. Alternatively, cell culture approaches remain important in the field and allow for personalized approaches, and scientific rigor can be ensured by authentication of cell lines.
Conclusions
Research in BE and EAC remains highly relevant given the morbidity and mortality associated with cancers of the tubular esophagus and gastroesophageal junction. Careful selection of models and inclusion of human samples whenever possible will ensure relevance to human health and disease.
背景与目的：本综述旨在全面、有效地更新与食管变性、发育不良和癌变相关的模型，重点关注巴雷特食管（BE）和食管腺癌（EAC）不同模型的优势和局限性：这篇专家综述是在全面查阅文献的基础上撰写的，并结合了专家对该领域现状的解读。我们强调了 2012-2023 年间的研究进展，并提供了与已建立的人类食管细胞系特征相关的详细信息：结果：利用患者样本和单细胞方法，我们对 BE 和 EAC 的发病机制有了新的认识。相关的动物模型包括遗传和外科小鼠模型，强调小鼠胃部鳞状结肠交界处（SCJ）病变的发展。大鼠模型是通过直接连接小肠和食道的手术方法产生的。大型动物模型的优点是能包含人类食道的特征，如食道粘膜下腺体（ESMGs）。另外，细胞培养方法在该领域仍然非常重要，它允许采用个性化方法，而且通过对细胞系进行鉴定可以确保科学的严谨性：鉴于与管状食管和胃食管交界处癌症相关的发病率和死亡率，对 BE 和 EAC 的研究仍具有高度相关性。谨慎选择模型并尽可能纳入人类样本将确保研究与人类健康和疾病相关。
{"title":"Promises and Limitations of Current Models for Understanding Barrett’s Esophagus and Esophageal Adenocarcinoma","authors":"Omar Martinez-Uribe , Thomas C. Becker , Katherine S. Garman","doi":"10.1016/j.jcmgh.2024.01.017","DOIUrl":"10.1016/j.jcmgh.2024.01.017","url":null,"abstract":"<div><h3>Background & Aims</h3><p>This review was developed to provide a thorough and effective update on models relevant to esophageal metaplasia, dysplasia, and carcinogenesis, focusing on the advantages and limitations of different models of Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC).</p></div><div><h3>Methods</h3><p>This expert review was written on the basis of a thorough review of the literature combined with expert interpretation of the state of the field. We emphasized advances over the years 2012–2023 and provided detailed information related to the characterization of established human esophageal cell lines.</p></div><div><h3>Results</h3><p>New insights have been gained into the pathogenesis of BE and EAC using patient-derived samples and single-cell approaches. Relevant animal models include genetic as well as surgical mouse models and emphasize the development of lesions at the squamocolumnar junction in the mouse stomach. Rat models are generated using surgical approaches that directly connect the small intestine and esophagus. Large animal models have the advantage of including features in human esophagus such as esophageal submucosal glands. Alternatively, cell culture approaches remain important in the field and allow for personalized approaches, and scientific rigor can be ensured by authentication of cell lines.</p></div><div><h3>Conclusions</h3><p>Research in BE and EAC remains highly relevant given the morbidity and mortality associated with cancers of the tubular esophagus and gastroesophageal junction. Careful selection of models and inclusion of human samples whenever possible will ensure relevance to human health and disease.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24000201/pdfft?md5=02615a07a567c8760236e308035da1af&pid=1-s2.0-S2352345X24000201-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139704136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.1016/j.jcmgh.2024.05.008
Huiyuan Xie , Haiyan Deng , Xiaoping Yang , Xianxian Gao , Shanru Yang , Weiyi Chen , Yixuan Wang , Naibin Yang , Liang Yong , Xin Hou
Background & Aims
The immune tolerance induced by hepatitis B virus (HBV) is a major challenge for achieving effective viral clearance, and the mechanisms involved are not well-understood. One potential factor involved in modulating immune responses is mesencephalic astrocyte-derived neurotrophic factor (MANF), which has been reported to be increased in patients with chronic hepatitis B. In this study, our objective is to examine the role of MANF in regulating immune responses to HBV.
Methods
We utilized a commonly used HBV-harboring mouse model, where mice were hydrodynamically injected with the pAAV/HBV1.2 plasmid. We assessed the HBV load by measuring the levels of various markers including hepatitis B surface antigen, hepatitis B envelope antigen, hepatitis B core antigen, HBV DNA, and HBV RNA.
Results
Our study revealed that following HBV infection, both myeloid cells and hepatocytes exhibited increased expression of MANF. Moreover, we observed that mice with myeloid-specific MANF knockout (ManfMye-/-) displayed reduced HBV load and improved HBV-specific T cell responses. The decreased HBV-induced tolerance in ManfMye-/- mice was associated with reduced accumulation of myeloid-derived suppressor cells (MDSCs) in the liver. Restoring MDSC levels in ManfMye-/- mice through MDSC adoptive transfer reinstated HBV-induced tolerance. Mechanistically, we found that MANF promoted MDSC expansion by activating the IL-6/STAT3 pathway. Importantly, our study demonstrated the effectiveness of a combination therapy involving an hepatitis B surface antigen vaccine and nanoparticle-encapsulated MANF siRNA in effectively clearing HBV in HBV-carrier mice.
Conclusion
The current study reveals that MANF plays a previously unrecognized regulatory role in liver tolerance by expanding MDSCs in the liver through IL-6/STAT3 signaling, leading to MDSC-mediated CD8+ T cell exhaustion.
{"title":"Mesencephalic Astrocyte-derived Neurotrophic Factor Supports Hepatitis B Virus-induced Immunotolerance","authors":"Huiyuan Xie , Haiyan Deng , Xiaoping Yang , Xianxian Gao , Shanru Yang , Weiyi Chen , Yixuan Wang , Naibin Yang , Liang Yong , Xin Hou","doi":"10.1016/j.jcmgh.2024.05.008","DOIUrl":"10.1016/j.jcmgh.2024.05.008","url":null,"abstract":"<div><h3>Background & Aims</h3><p>The immune tolerance induced by hepatitis B virus (HBV) is a major challenge for achieving effective viral clearance, and the mechanisms involved are not well-understood. One potential factor involved in modulating immune responses is mesencephalic astrocyte-derived neurotrophic factor (MANF), which has been reported to be increased in patients with chronic hepatitis B. In this study, our objective is to examine the role of MANF in regulating immune responses to HBV.</p></div><div><h3>Methods</h3><p>We utilized a commonly used HBV-harboring mouse model, where mice were hydrodynamically injected with the pAAV/HBV1.2 plasmid. We assessed the HBV load by measuring the levels of various markers including hepatitis B surface antigen, hepatitis B envelope antigen, hepatitis B core antigen, HBV DNA, and HBV RNA.</p></div><div><h3>Results</h3><p>Our study revealed that following HBV infection, both myeloid cells and hepatocytes exhibited increased expression of MANF. Moreover, we observed that mice with myeloid-specific MANF knockout (Manf<sup>Mye-/-</sup>) displayed reduced HBV load and improved HBV-specific T cell responses. The decreased HBV-induced tolerance in Manf<sup>Mye-/-</sup> mice was associated with reduced accumulation of myeloid-derived suppressor cells (MDSCs) in the liver. Restoring MDSC levels in Manf<sup>Mye-/-</sup> mice through MDSC adoptive transfer reinstated HBV-induced tolerance. Mechanistically, we found that MANF promoted MDSC expansion by activating the IL-6/STAT3 pathway. Importantly, our study demonstrated the effectiveness of a combination therapy involving an hepatitis B surface antigen vaccine and nanoparticle-encapsulated MANF siRNA in effectively clearing HBV in HBV-carrier mice.</p></div><div><h3>Conclusion</h3><p>The current study reveals that MANF plays a previously unrecognized regulatory role in liver tolerance by expanding MDSCs in the liver through IL-6/STAT3 signaling, leading to MDSC-mediated CD8<sup>+</sup> T cell exhaustion.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24001140/pdfft?md5=43d4376f89a1060ffb852ae42d8ee968&pid=1-s2.0-S2352345X24001140-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140961077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.1016/j.jcmgh.2023.12.011
Johanna Reißing , Marie Berres , Pavel Strnad , Alexander Wree , Maria Eugenia Inzaugarat , Christian Trautwein , Tony Bruns , Henning Wolfgang Zimmermann
Background & Aims
Type 2 immune responses contribute to liver fibrosis in parasite infections, but their role in other liver diseases is less well understood. Here, we aimed at unravelling mechanisms involved in T helper 2 (Th2) T-cell polarization, activation, and recruitment in human liver fibrosis and cirrhosis.
Methods
Tissues, cells, and serum from human livers were analyzed using quantitative reverse-transcription polymerase chain reaction, enzyme-linked immunosorbent assay, fluorescence in situ hybridization, immunostaining, flow cytometry, and various functional in vitro assays. Cellular interactions and soluble mediators involved in T-cell polarization and recruitment were studied, as well as their effect on hepatic stellate cell (HSC) activation, proliferation, and extracellular matrix synthesis.
Results
In human liver fibrosis, a stage-dependent increase in Th2-related transcription factors, Th2 cytokines, and trans-acting T-cell–specific transcription factor–expressing T cells was observed, and was highest in cirrhotic livers. The alarmin interleukin (IL)33 was found to be increased in livers and sera from patients with cirrhosis, to act as a chemotactic agent for Th2 cells, and to induce type 2 polarization of CD4+ T cells. Oval cells, liver sinusoidal endothelial cells, intrahepatic macrophages, and migrating monocytes were identified as sources of IL33. IL33-activated T cells, but not IL33 alone, induced HSC activation, as shown by Ki67 and α-smooth muscle actin staining, increased collagen type I alpha 1 chain messenger RNA expression, and wound healing assays. The profibrotic effect of IL33-activated T cells was contact-independent and could be antagonized using monoclonal antibodies against IL13.
Conclusion
In patients with chronic liver disease, the alarmin IL33 promotes the recruitment and activation of CD4+ T cells with Th2-like properties, which activate paracrine HSC in an IL13-dependent manner and promotes fibrogenesis.
背景& 目的Th2免疫反应在寄生虫感染中导致肝纤维化，但它们在其他肝病中的作用还不太清楚。方法 使用 qRT-PCR、ELISA、FISH、免疫染色、流式细胞术和各种体外功能测试分析人肝脏的组织、细胞和血清。研究了参与 T 细胞极化和招募的细胞相互作用和可溶性介质，以及它们对肝星状细胞（HSC）活化、增殖和细胞外基质合成的影响。结果在人类肝纤维化中，观察到 Th2 相关转录因子、Th2 细胞因子和 GATA3 表达 T 细胞的增加呈阶段依赖性，在肝硬化中增幅最大。研究发现，肝硬化患者的肝脏和血清中警戒素 IL-33 增加，可作为 Th2 细胞的趋化因子，并诱导 CD4+ T 细胞的 2 型极化。卵圆形细胞、肝窦内皮细胞、肝内巨噬细胞和迁移的单核细胞被确定为 IL-33 的来源。通过Ki67和α-SMA染色、COL1A1 mRNA表达增加和伤口愈合试验证明，IL-33激活的T细胞而非单独的IL-33可诱导造血干细胞活化。结论在慢性肝病患者中，警戒素 IL-33 可促进具有 Th2 类特性的 CD4+ T 细胞的募集和活化，从而以 IL-13 依赖性方式激活旁分泌型造血干细胞并促进纤维化。
{"title":"Th2 Cell Activation in Chronic Liver Disease Is Driven by Local IL33 and Contributes to IL13-Dependent Fibrogenesis","authors":"Johanna Reißing , Marie Berres , Pavel Strnad , Alexander Wree , Maria Eugenia Inzaugarat , Christian Trautwein , Tony Bruns , Henning Wolfgang Zimmermann","doi":"10.1016/j.jcmgh.2023.12.011","DOIUrl":"10.1016/j.jcmgh.2023.12.011","url":null,"abstract":"<div><h3>Background & Aims</h3><p>Type 2 immune responses contribute to liver fibrosis in parasite infections, but their role in other liver diseases is less well understood. Here, we aimed at unravelling mechanisms involved in T helper 2 (Th2) T-cell polarization, activation, and recruitment in human liver fibrosis and cirrhosis.</p></div><div><h3>Methods</h3><p>Tissues, cells, and serum from human livers were analyzed using quantitative reverse-transcription polymerase chain reaction, enzyme-linked immunosorbent assay, fluorescence in situ hybridization, immunostaining, flow cytometry, and various functional in vitro assays. Cellular interactions and soluble mediators involved in T-cell polarization and recruitment were studied, as well as their effect on hepatic stellate cell (HSC) activation, proliferation, and extracellular matrix synthesis.</p></div><div><h3>Results</h3><p>In human liver fibrosis, a stage-dependent increase in Th2-related transcription factors, Th2 cytokines, and trans-acting T-cell–specific transcription factor–expressing T cells was observed, and was highest in cirrhotic livers. The alarmin interleukin (IL)33 was found to be increased in livers and sera from patients with cirrhosis, to act as a chemotactic agent for Th2 cells, and to induce type 2 polarization of CD4+ T cells. Oval cells, liver sinusoidal endothelial cells, intrahepatic macrophages, and migrating monocytes were identified as sources of IL33. IL33-activated T cells, but not IL33 alone, induced HSC activation, as shown by Ki67 and α-smooth muscle actin staining, increased collagen type I alpha 1 chain messenger RNA expression, and wound healing assays. The profibrotic effect of IL33-activated T cells was contact-independent and could be antagonized using monoclonal antibodies against IL13.</p></div><div><h3>Conclusion</h3><p>In patients with chronic liver disease, the alarmin IL33 promotes the recruitment and activation of CD4+ T cells with Th2-like properties, which activate paracrine HSC in an IL13-dependent manner and promotes fibrogenesis.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X23002278/pdfft?md5=2e5b8335236214bf8d30b1dc63316401&pid=1-s2.0-S2352345X23002278-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139054066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Colorectal cancer (CRC) is the third most common cancer in the world. Gut microbiota has recently been implicated in the development of CRC. Actinomyces odontolyticus is one of the most abundant bacteria in the gut of patients with very early stages of CRC. A odontolyticus is an anaerobic bacterium existing principally in the oral cavity, similar to Fusobacterium nucleatum, which is known as a colon carcinogenic bacterium. Here we newly determined the biological functions of A odontolyticus on colonic oncogenesis.
Methods
We examined the induction of intracellular signaling by A odontolyticus in human colonic epithelial cells (CECs). DNA damage levels in CECs were confirmed using the human induced pluripotent stem cell-derived gut organoid model and mouse colon tissues in vivo.
Results
A odontolyticus secretes membrane vesicles (MVs), which induce nuclear factor kappa B signaling and also produce excessive reactive oxygen species (ROS) in colon epithelial cells. We found that A odontolyticus secretes lipoteichoic acid-rich MVs, promoting inflammatory signaling via TLR2. Simultaneously, those MVs are internalized into the colon epithelial cells, co-localize with the mitochondria, and cause mitochondrial dysfunction, resulting in excessive ROS production and DNA damage. Induction of excessive DNA damage in colonic cells by A odontolyticus-derived MVs was confirmed in the gut organoid model and also in mouse colon tissues.
Conclusions
A odontolyticus secretes MVs, which cause chronic inflammation and ROS production in colonic epithelial cells, leading to the initiation of CRC.
{"title":"Gut Bacteria-derived Membrane Vesicles Induce Colonic Dysplasia by Inducing DNA Damage in Colon Epithelial Cells","authors":"Yu Miyakawa , Motoyuki Otsuka , Chikako Shibata , Takahiro Seimiya , Keisuke Yamamoto , Rei Ishibashi , Takahiro Kishikawa , Eri Tanaka , Takayuki Isagawa , Norihiko Takeda , Noriaki Kamio , Kenichi Imai , Mitsuhiro Fujishiro","doi":"10.1016/j.jcmgh.2024.01.010","DOIUrl":"10.1016/j.jcmgh.2024.01.010","url":null,"abstract":"<div><h3>Background & Aims</h3><p>Colorectal cancer (CRC) is the third most common cancer in the world. Gut microbiota has recently been implicated in the development of CRC. <em>Actinomyces odontolyticus</em> is one of the most abundant bacteria in the gut of patients with very early stages of CRC. <em>A odontolyticus</em> is an anaerobic bacterium existing principally in the oral cavity, similar to <em>Fusobacterium nucleatum,</em> which is known as a colon carcinogenic bacterium. Here we newly determined the biological functions of <em>A odontolyticus</em> on colonic oncogenesis.</p></div><div><h3>Methods</h3><p>We examined the induction of intracellular signaling by <em>A odontolyticus</em> in human colonic epithelial cells (CECs). DNA damage levels in CECs were confirmed using the human induced pluripotent stem cell-derived gut organoid model and mouse colon tissues in vivo.</p></div><div><h3>Results</h3><p><em>A odontolyticus</em> secretes membrane vesicles (MVs), which induce nuclear factor kappa B signaling and also produce excessive reactive oxygen species (ROS) in colon epithelial cells. We found that <em>A odontolyticus</em> secretes lipoteichoic acid-rich MVs, promoting inflammatory signaling via TLR2. Simultaneously, those MVs are internalized into the colon epithelial cells, co-localize with the mitochondria, and cause mitochondrial dysfunction, resulting in excessive ROS production and DNA damage. Induction of excessive DNA damage in colonic cells by <em>A odontolyticus</em>-derived MVs was confirmed in the gut organoid model and also in mouse colon tissues.</p></div><div><h3>Conclusions</h3><p><em>A odontolyticus</em> secretes MVs, which cause chronic inflammation and ROS production in colonic epithelial cells, leading to the initiation of CRC.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24000109/pdfft?md5=e23ca47bd954111738ee31e9c0a144d5&pid=1-s2.0-S2352345X24000109-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139668490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Inflammatory bowel disease is associated with carcinogenesis, which limits the prognosis of the patients. The local expression of proteinases and proteinase-activated receptor 1 (PAR1) increases in inflammatory bowel disease. The present study investigated the therapeutic effects of PAR1 antagonism on colitis-associated carcinogenesis.
Methods
A colitis-associated carcinogenesis model was prepared in mice by treatment with azoxymethane (AOM) and dextran sulfate sodium (DSS). PAR1 antagonist E5555 was administered in long- and short-term protocol, starting on the day of AOM injection and 1 week after completing AOM/DSS treatment, respectively. The fecal samples were collected for metagenome analysis of gut microbiota. The intestinal myofibroblasts of the Crohn’s disease patients were used to elucidate underlying cellular mechanisms. Caco-2 cells were used to investigate a possible source of PAR1 agonist proteinases.
Results
AOM/DSS model showed weight loss, diarrhea, tumor development, inflammation, fibrosis, and increased production of inflammatory cytokines. The β-diversity, but not α-diversity, of microbiota significantly differed between AOM/DSS and control mice. E5555 alleviated these pathological changes and altered the microbiota β-diversity in AOM/DSS mice. The thrombin expression was up-regulated in tumor and non-tumor areas, whereas PAR1 mRNA expression was higher in tumor areas compared with non-tumor areas. E5555 inhibited thrombin-triggered elevation of cytosolic Ca2+ concentration and ERK1/2 phosphorylation, as well as IL6-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation in intestinal myofibroblasts. Caco-2 cell-conditioned medium contained immunoreactive thrombin, which cleaved the recombinant protein containing the extracellular domain of PAR1 at the thrombin cleavage site.
Conclusions
PAR1 antagonism is proposed to be a novel therapeutic strategy for treatment of inflammatory bowel disease and its associated carcinogenesis.
{"title":"Therapeutic Effect of Proteinase-Activated Receptor-1 Antagonist on Colitis-Associated Carcinogenesis","authors":"Xiaodong Li , Lin-Hai Kurahara , Zhixin Zhao , Feiyan Zhao , Ryo Ishikawa , Kiyomi Ohmichi , Gaopeng Li , Tetsuo Yamashita , Takeshi Hashimoto , Mayumi Hirano , Zhihong Sun , Katsuya Hirano","doi":"10.1016/j.jcmgh.2024.04.001","DOIUrl":"10.1016/j.jcmgh.2024.04.001","url":null,"abstract":"<div><h3>Background & Aims</h3><p>Inflammatory bowel disease is associated with carcinogenesis, which limits the prognosis of the patients. The local expression of proteinases and proteinase-activated receptor 1 (PAR<sub>1</sub>) increases in inflammatory bowel disease. The present study investigated the therapeutic effects of PAR<sub>1</sub> antagonism on colitis-associated carcinogenesis.</p></div><div><h3>Methods</h3><p>A colitis-associated carcinogenesis model was prepared in mice by treatment with azoxymethane (AOM) and dextran sulfate sodium (DSS). PAR<sub>1</sub> antagonist E5555 was administered in long- and short-term protocol, starting on the day of AOM injection and 1 week after completing AOM/DSS treatment, respectively. The fecal samples were collected for metagenome analysis of gut microbiota. The intestinal myofibroblasts of the Crohn’s disease patients were used to elucidate underlying cellular mechanisms. Caco-2 cells were used to investigate a possible source of PAR<sub>1</sub> agonist proteinases.</p></div><div><h3>Results</h3><p>AOM/DSS model showed weight loss, diarrhea, tumor development, inflammation, fibrosis, and increased production of inflammatory cytokines. The β-diversity, but not α-diversity, of microbiota significantly differed between AOM/DSS and control mice. E5555 alleviated these pathological changes and altered the microbiota β-diversity in AOM/DSS mice. The thrombin expression was up-regulated in tumor and non-tumor areas, whereas PAR<sub>1</sub> mRNA expression was higher in tumor areas compared with non-tumor areas. E5555 inhibited thrombin-triggered elevation of cytosolic Ca<sup>2+</sup> concentration and ERK1/2 phosphorylation, as well as IL6-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation in intestinal myofibroblasts. Caco-2 cell-conditioned medium contained immunoreactive thrombin, which cleaved the recombinant protein containing the extracellular domain of PAR<sub>1</sub> at the thrombin cleavage site.</p></div><div><h3>Conclusions</h3><p>PAR<sub>1</sub> antagonism is proposed to be a novel therapeutic strategy for treatment of inflammatory bowel disease and its associated carcinogenesis.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24000717/pdfft?md5=8b994d1d5ae16166b21f33644cff1753&pid=1-s2.0-S2352345X24000717-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140790423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.1016/j.jcmgh.2024.02.016
Julie Pabois , Tony Durand , Catherine Le Berre , Rhiannon T. Filippone , Théo Noël , Emilie Durieu , Céline Bossard , Sarah Bruneau , Malvyne Rolli-Derkinderen , Kulmira Nurgali , Michel Neunlist , Arnaud Bourreille , Isabelle Neveu , Philippe Naveilhan
Background & Aims
The presence of myenteric plexitis in the proximal resection margins is a predictive factor of early postoperative recurrence in Crohn’s disease. To decipher the mechanisms leading to their formation, T-cell interactions with enteric neural cells were studied in vitro and in vivo.
Methods
T cells close to myenteric neural cells were retrospectively quantified in ileocolonic resections from 9 control subjects with cancer and 20 patients with Crohn’s disease. The mechanisms involved in T-cell adhesion were then investigated in co-cultures of T lymphocytes with enteric glial cells (glia). Finally, the implication of adhesion molecules in the development of plexitis and colitis was studied in vitro but also in vivo in Winnie mice.
Results
The mean number of T cells close to glia, but not neurons, was significantly higher in the myenteric ganglia of relapsing patients with Crohn’s disease (2.42 ± 0.5) as compared with controls (0.36 ± 0.08, P = .0007). Co-culture experiments showed that exposure to proinflammatory cytokines enhanced T-cell adhesion to glia and increased intercellular adhesion molecule-1 (ICAM-1) expression in glia. We next demonstrated that T-cell adhesion to glia was inhibited by an anti–ICAM-1 antibody. Finally, using the Winnie mouse model of colitis, we showed that the blockage of ICAM-1/lymphocyte function-associated antigen-1 (LFA-1) with lifitegrast reduced colitis severity and decreased T-cell infiltration in the myenteric plexus.
Conclusions
Our present work argues for a role of glia–T-cell interaction in the development of myenteric plexitis through the adhesion molecules ICAM-1/LFA-1 and suggests that deciphering the functional consequences of glia–T-cell interaction is important to understand the mechanisms implicated in the development and recurrence of Crohn’s disease.
背景与目的：近端切除边缘出现肠系膜神经丛炎是克罗恩病术后早期复发的一个预测因素。为了破译导致其形成的机制，我们在体外和体内研究了 T 细胞与肠神经细胞的相互作用：方法：对 9 名癌症对照组患者和 20 名克罗恩病患者的回结肠切除术中靠近肠神经细胞的 T 细胞进行了回顾性定量分析。然后，在 T 淋巴细胞与肠胶质细胞（glia）的共培养物中研究了 T 细胞粘附的机制。最后，不仅在体外，还在 Winnie 小鼠体内研究了粘附分子在丛神经炎和结肠炎发病过程中的作用：结果：与对照组（0.36+/-0.08，P=0.0007）相比，克罗恩病复发患者肠肌节中靠近神经胶质而非神经元的 T 细胞的平均数量显著增加（2.42+/-0.5）。共培养实验表明，暴露于促炎细胞因子会增强 T 细胞对神经胶质的粘附，并增加神经胶质中 ICAM-1 的表达。我们接下来证明，抗 ICAM-1 抗体可抑制 T 细胞粘附到胶质细胞。最后，我们利用 Winnie 小鼠结肠炎模型证明，用利菲格拉司特阻断 ICAM-1/ LFA-1 可降低结肠炎的严重程度，并减少肠肌丛中的 T 细胞浸润：我们目前的工作证明了神经胶质-T 细胞相互作用通过粘附分子 ICAM-1/LFA-1 在肠系膜神经丛炎的发生发展中的作用，并表明破译神经胶质-T 细胞相互作用的功能性后果对于了解克罗恩病的发生发展和复发机制非常重要。
{"title":"Role of ICAM-1 in the Adhesion of T Cells to Enteric Glia: Perspectives in the Formation of Plexitis in Crohn’s Disease","authors":"Julie Pabois , Tony Durand , Catherine Le Berre , Rhiannon T. Filippone , Théo Noël , Emilie Durieu , Céline Bossard , Sarah Bruneau , Malvyne Rolli-Derkinderen , Kulmira Nurgali , Michel Neunlist , Arnaud Bourreille , Isabelle Neveu , Philippe Naveilhan","doi":"10.1016/j.jcmgh.2024.02.016","DOIUrl":"10.1016/j.jcmgh.2024.02.016","url":null,"abstract":"<div><h3>Background & Aims</h3><p>The presence of myenteric plexitis in the proximal resection margins is a predictive factor of early postoperative recurrence in Crohn’s disease. To decipher the mechanisms leading to their formation, T-cell interactions with enteric neural cells were studied in vitro and in vivo.</p></div><div><h3>Methods</h3><p>T cells close to myenteric neural cells were retrospectively quantified in ileocolonic resections from 9 control subjects with cancer and 20 patients with Crohn’s disease. The mechanisms involved in T-cell adhesion were then investigated in co-cultures of T lymphocytes with enteric glial cells (glia). Finally, the implication of adhesion molecules in the development of plexitis and colitis was studied in vitro but also in vivo in Winnie mice.</p></div><div><h3>Results</h3><p>The mean number of T cells close to glia, but not neurons, was significantly higher in the myenteric ganglia of relapsing patients with Crohn’s disease (2.42 ± 0.5) as compared with controls (0.36 ± 0.08, <em>P</em> = .0007). Co-culture experiments showed that exposure to proinflammatory cytokines enhanced T-cell adhesion to glia and increased intercellular adhesion molecule-1 (ICAM-1) expression in glia. We next demonstrated that T-cell adhesion to glia was inhibited by an anti–ICAM-1 antibody. Finally, using the Winnie mouse model of colitis, we showed that the blockage of ICAM-1/lymphocyte function-associated antigen-1 (LFA-1) with lifitegrast reduced colitis severity and decreased T-cell infiltration in the myenteric plexus.</p></div><div><h3>Conclusions</h3><p>Our present work argues for a role of glia–T-cell interaction in the development of myenteric plexitis through the adhesion molecules ICAM-1/LFA-1 and suggests that deciphering the functional consequences of glia–T-cell interaction is important to understand the mechanisms implicated in the development and recurrence of Crohn’s disease.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X2400050X/pdfft?md5=da24d11348be30a3d1f546e383c7dccf&pid=1-s2.0-S2352345X2400050X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140013771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.1016/j.jcmgh.2023.10.011
Ikki Sakuma, Daniel F. Vatner
{"title":"Fatty Acid Esterification as a NASH Therapeutic Target","authors":"Ikki Sakuma, Daniel F. Vatner","doi":"10.1016/j.jcmgh.2023.10.011","DOIUrl":"10.1016/j.jcmgh.2023.10.011","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X2300190X/pdfft?md5=2a16e99e77d59699d75db91baafb36f5&pid=1-s2.0-S2352345X2300190X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138178095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.1016/j.jcmgh.2024.05.009
Alexandra Demcsák, Miklós Sahin-Tóth
Background & Aims
Heterozygous SPINK1 mutations are strong risk factors for chronic pancreatitis in humans, yet heterozygous disruption of mouse Spink1 yielded no pancreatic phenotype. To resolve this contradiction, we used CRISPR/Cas9-mediated genome editing to generate heterozygous Spink1-deleted mice (Spink1-KOhet) in the C57BL/6N strain and studied the effect of this allele in trypsin-independent and trypsin-dependent pancreatitis models.
Methods
We investigated severity of acute pancreatitis and progression to chronic pancreatitis in Spink1-KOhet mice after transient (10 injections) and prolonged (2 × 8 injections) cerulein hyperstimulation. We crossed Spink1-KOhet mice with T7D23A and T7D22N,K24R mice that carry strongly autoactivating trypsinogen mutants and exhibit spontaneous chronic pancreatitis.
Results
Prolonged but not transient cerulein stimulation resulted in increased intrapancreatic trypsin activity and more severe acute pancreatitis in Spink1-KOhet mice relative to the C57BL/6N control strain. After the acute episode, Spink1-KOhet mice developed progressive disease with chronic pancreatitis-like features, whereas C57BL/6N mice recovered rapidly. Trypsinogen mutant mice carrying the Spink1-KOhet allele exhibited strikingly more severe chronic pancreatitis than the respective parent strains.
Conclusions
Heterozygous Spink1 deficiency caused more severe acute pancreatitis after prolonged cerulein stimulation and promoted chronic pancreatitis after the cerulein-induced acute episode, and in two strains of trypsinogen mutant mice with spontaneous disease. In contrast, acute pancreatitis induced with limited cerulein hyperstimulation was unaffected by heterozygous Spink1 deletion, in agreement with recent observations that trypsin activity does not mediate pathologic responses in this model. Taken together, the findings strongly support the notion that loss-of-function SPINK1 mutations in humans increase chronic pancreatitis risk in a trypsin-dependent manner.
{"title":"Heterozygous Spink1 Deficiency Promotes Trypsin-dependent Chronic Pancreatitis in Mice","authors":"Alexandra Demcsák, Miklós Sahin-Tóth","doi":"10.1016/j.jcmgh.2024.05.009","DOIUrl":"10.1016/j.jcmgh.2024.05.009","url":null,"abstract":"<div><h3>Background & Aims</h3><p>Heterozygous <em>SPINK1</em> mutations are strong risk factors for chronic pancreatitis in humans, yet heterozygous disruption of mouse <em>Spink1</em> yielded no pancreatic phenotype. To resolve this contradiction, we used CRISPR/Cas9-mediated genome editing to generate heterozygous <em>Spink1</em>-deleted mice (<em>Spink1-KO</em><sup>het</sup>) in the C57BL/6N strain and studied the effect of this allele in trypsin-independent and trypsin-dependent pancreatitis models.</p></div><div><h3>Methods</h3><p>We investigated severity of acute pancreatitis and progression to chronic pancreatitis in <em>Spink1-KO</em><sup>het</sup> mice after transient (10 injections) and prolonged (2 × 8 injections) cerulein hyperstimulation. We crossed <em>Spink1-KO</em><sup>het</sup> mice with <em>T7D23A</em> and <em>T7D22N,K24R</em> mice that carry strongly autoactivating trypsinogen mutants and exhibit spontaneous chronic pancreatitis.</p></div><div><h3>Results</h3><p>Prolonged but not transient cerulein stimulation resulted in increased intrapancreatic trypsin activity and more severe acute pancreatitis in <em>Spink1-KO</em><sup>het</sup> mice relative to the C57BL/6N control strain. After the acute episode, <em>Spink1-KO</em><sup>het</sup> mice developed progressive disease with chronic pancreatitis-like features, whereas C57BL/6N mice recovered rapidly. Trypsinogen mutant mice carrying the <em>Spink1-KO</em><sup>het</sup> allele exhibited strikingly more severe chronic pancreatitis than the respective parent strains.</p></div><div><h3>Conclusions</h3><p>Heterozygous <em>Spink1</em> deficiency caused more severe acute pancreatitis after prolonged cerulein stimulation and promoted chronic pancreatitis after the cerulein-induced acute episode, and in two strains of trypsinogen mutant mice with spontaneous disease. In contrast, acute pancreatitis induced with limited cerulein hyperstimulation was unaffected by heterozygous <em>Spink1</em> deletion, in agreement with recent observations that trypsin activity does not mediate pathologic responses in this model. Taken together, the findings strongly support the notion that loss-of-function <em>SPINK1</em> mutations in humans increase chronic pancreatitis risk in a trypsin-dependent manner.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24001152/pdfft?md5=fcd6a6d57f664b7a4d6aa24940431b9c&pid=1-s2.0-S2352345X24001152-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141072312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.1016/j.jcmgh.2024.03.011
Brian D. Gulbransen
{"title":"The Ties That Bind: Enteric Glia Link T Cells to Plexitis in Crohn’s","authors":"Brian D. Gulbransen","doi":"10.1016/j.jcmgh.2024.03.011","DOIUrl":"10.1016/j.jcmgh.2024.03.011","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24000663/pdfft?md5=bc37fdfdc8cfce1639d80afc44f7ab54&pid=1-s2.0-S2352345X24000663-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140855773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.1016/j.jcmgh.2024.05.011
{"title":"Scaffolding Supports the Hippo","authors":"","doi":"10.1016/j.jcmgh.2024.05.011","DOIUrl":"10.1016/j.jcmgh.2024.05.011","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24001176/pdfft?md5=61597794f1bd71f3236b26e48d5ddba2&pid=1-s2.0-S2352345X24001176-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141288927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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