Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
Laboratorio de Inmunología Experimental y Regulación de la Inflamación Hepato-Intestinal, UBIMED, FES Iztacala UNAM, Estado de México, Mexico.
Sci Rep. 2018 Feb 15;8(1):3127. doi: 10.1038/s41598-018-21112-7.
Obesity is a global epidemic affecting chronic inflammatory diseases. Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease that can occur as an extraintestinal manifestation of inflammatory bowel disease (IBD). Previously we reported that patients with PSC who are obese have a higher risk of advanced liver disease. Currently it is unknown how obesity accelerates or worsens PSC. We evaluated the progression of PSC in an antigen-driven cholangitis mouse model of diet-induced obesity. Obesity was induced in our murine model of immune-mediated cholangitis (OVAbil). OVAbil mice were fed standard chow or high-fat/sucrose diet for twelve weeks followed by induction of biliary inflammation by OVA-specific T cell transfer. Histopathological damage in portal tracts was scored and serum collected. Neutralizing antibodies against IL-15 were administered daily until study termination. Obese mice developed exacerbated liver inflammation and damage. Immune cell phenotyping in liver revealed greater numbers of neutrophils and CD8+ T cells in obese mice. Higher levels of cytokines and chemokines were found in obese mice with cholangitis. Immuno-neutralizing antibodies against IL-15 greatly attenuated cholangitis in obese mice. Obesity exacerbated experimental PSC in part by overproduction of IL-15. Timely targeting of IL-15 may slow the progression of PSC.
肥胖是一种全球性的流行病，会影响慢性炎症性疾病。原发性硬化性胆管炎 (PSC) 是一种慢性胆汁淤积性肝病，可作为炎症性肠病 (IBD) 的肠外表现。此前我们曾报道过，肥胖的 PSC 患者发生晚期肝病的风险更高。目前尚不清楚肥胖如何加速或加重 PSC。我们在饮食诱导肥胖的抗原驱动性胆管炎小鼠模型中评估了 PSC 的进展。在我们的免疫介导性胆管炎小鼠模型（OVAbil）中诱导肥胖。OVAbil 小鼠喂食标准饲料或高脂肪/蔗糖饮食 12 周，然后通过 OVA 特异性 T 细胞转移诱导胆管炎症。对门脉区的组织病理学损伤进行评分并收集血清。在研究结束前，每天给予中和抗 IL-15 抗体。肥胖小鼠出现更严重的肝脏炎症和损伤。肝脏免疫细胞表型分析显示肥胖小鼠中性粒细胞和 CD8+T 细胞数量增加。肥胖胆管炎小鼠的细胞因子和趋化因子水平升高。抗 IL-15 的免疫中和抗体可显著减轻肥胖小鼠的胆管炎。肥胖通过过度产生 IL-15 加重实验性 PSC。及时靶向 IL-15 可能会减缓 PSC 的进展。
