促炎细胞因子
炎症性肠病
结肠炎
透明质酸合成酶
炎症
免疫学
肿瘤坏死因子α
免疫系统
溃疡性结肠炎
透明质酸
医学
癌症研究
病理
疾病
解剖
作者
Christian Hundhausen,Rebekka Schneckmann,Yanina Ostendorf,Jacqueline Rimpler,Anette von Glinski,Christina Kohlmorgen,Nina Pasch,Luca Rolauer,Florian von Ameln,Olaf Eckermann,Joachim Altschmied,Niloofar Ale‐Agha,Judith Haendeler,Ulrich Flögel,Jens W. Fischer,Maria Grandoch
标识
DOI:10.1016/j.matbio.2021.08.001
摘要
The association between hyaluronan (HA) accumulation and increased inflammation in the colon suggests that HA is a potential therapeutic target in inflammatory bowel disease (IBD). However, whether patients with IBD would benefit from interference with HA synthesis is unknown. Here, we used pharmacological and genetic approaches to investigate the impact of systemic and partial blockade of HA synthesis in the Dextran Sodium Sulfate (DSS)-induced colitis model. To systemically inhibit HA production, we used 4-Methylumbelliferone (4-MU), whereas genetic approaches included the generation of mice with global or inducible cell-type specific deficiency in the Hyaluronan synthase 3 (Has3). We found that 4-MU treatment did not ameliorate but exacerbated disease severity characterized by increased body weight loss and enhanced colon tissue destruction compared to control mice without colitis. In contrast, global Has3 deficiency had a profound protective effect as reflected by a low colitis score and reduced infiltration of immune cells into the colon. To get further mechanistic insight into the proinflammatory role of HAS3, we deleted Has3 in a cell-type specific manner. Interestingly, while lack of Has3 expression in intestinal epithelial and smooth muscle cells had no effect or was rather proinflammatory, mice with Has3 deficiency in the endothelium were strongly protected against acute colitis. We conclude that endothelium-derived HAS3 plays a critical role in driving experimental colitis, warranting future studies on cell type-specific therapeutic interference with HA production in human IBD.
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