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.

透明质酸 (HA) 积累与结肠炎症增加之间的关联表明 HA 是炎症性肠病 (IBD) 的潜在治疗靶点。然而，IBD 患者是否会从干扰 HA 合成中获益尚不清楚。在这里，我们使用药理学和遗传学方法来研究在葡聚糖硫酸钠 (DSS) 诱导的结肠炎模型中系统性和部分阻断 HA 合成的影响。为了系统地抑制 HA 的产生，我们使用了 4-甲基伞形酮 (4-MU)，而遗传方法包括产生透明质酸合酶 3 ( Has3）。我们发现，与没有结肠炎的对照小鼠相比，4-MU 治疗并未改善但加重了疾病严重程度，其特征是体重减轻增加和结肠组织破坏增加。相比之下，整体 Has3缺乏具有深远的保护作用，表现为结肠炎评分低和免疫细胞向结肠的浸润减少。为了进一步深入了解 HAS3 的促炎作用，我们以细胞类型特异性方式删除了Has3。有趣的是，虽然在肠上皮和平滑肌细胞中缺乏Has3表达没有影响或相当促炎，但具有Has3的小鼠内皮细胞缺乏对急性结肠炎有很强的保护作用。我们得出结论，内皮衍生的 HAS3 在驱动实验性结肠炎中起关键作用，值得未来研究细胞类型特异性治疗干扰人类 IBD 中 HA 的产生。