Department of Physiology and Pharmacology, Inflammation Research Network, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada.
Department of Microbiology, Immunology and Infectious Diseases, Inflammation Research Network, Cumming School of Medicine, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada.
Front Immunol. 2019 Mar 26;10:557. doi: 10.3389/fimmu.2019.00557. eCollection 2019.
Inflammatory bowel disease (IBD) is characterized by both acute and chronic phase inflammation of the gastro-intestinal (GI) tract that affect a large and growing number of people worldwide with little to no effective treatments. This is in part due to the lack of understanding of the disease pathogenesis and also the currently poorly described involvement of other systems such as the lymphatics. During DSS induced colitis, mice also develop a severe inflammation of terminal ileum with many features similar to IBD. As well as inflammation within the ileum we have previously demonstrated lymphatic remodeling within the mesentery and mesenteric lymph nodes of DSS-treated mice. The lymphatic remodeling includes lymphangiogenesis, lymphatic vessel dilation and leakiness, as well as cellular infiltration into the surrounding tissue and peripheral draining lymph nodes. Intestinal inflammation was induced in C57BL/6 mice by administration of 2.5% DSS in drinking water for 7 days. Mice were treated with TLR4 blocker C34 or Polymyxin-B (PMXB) daily from days 3 to 7 of DSS treatment via I.P. injection, and their therapeutic effects on disease activity and lymphatic function were examined. TLR activity and subsequent effect on lymphangiogenesis, lymphadenopathy, and mesenteric lymph node cellular composition were assessed. DSS Mice treated with TLR4 inhibitor, C34, had a significantly improved disease phenotype characterized by reduced ileal and colonic insult. The change correlated with significant reduction in colonic and mesenteric inflammation, resolved mesenteric lymphangiectasia, and CD103 DC migration similar to that of healthy control. PMXB treatment however did not resolve inflammation within the colon or associated mesenteric lymphatic dysfunction but did however prevent lymphadenopathy within the MLN through alteration of CCL21 gradients and CD103 DC migration. TLR4 appears to mediate several changes within the mesenteric lymphatics, more specifically it is shown to have different outcomes whether stimulation occurs through pathogen derived factors such as LPS or tissue derived DAMPs, a novel phenomenon.
炎症性肠病（IBD）的特征是胃肠道（GI）的急性和慢性炎症，影响了全球大量的人，而有效的治疗方法却很少。这在一定程度上是由于对疾病发病机制的了解不足，也部分是由于目前对其他系统（如淋巴系统）的描述较差。在 DSS 诱导的结肠炎中，小鼠的末端回肠也会发生严重炎症，许多特征与 IBD 相似。除了回肠内的炎症，我们之前还证明了 DSS 治疗小鼠肠系膜和肠系膜淋巴结内的淋巴管重塑。淋巴管重塑包括淋巴管生成、淋巴管扩张和通透性增加，以及细胞浸润到周围组织和外周引流淋巴结。通过在饮用水中给予 2.5% DSS，在 C57BL/6 小鼠中诱导肠道炎症，持续 7 天。从 DSS 治疗的第 3 天到第 7 天，通过腹腔注射每天给 TLR4 阻断剂 C34 或多粘菌素 B（PMXB）治疗小鼠，并检查它们对疾病活动和淋巴管功能的治疗效果。评估 TLR 活性及其对淋巴管生成、淋巴结病和肠系膜淋巴结细胞组成的后续影响。用 TLR4 抑制剂 C34 治疗的 DSS 小鼠具有明显改善的疾病表型，表现为回肠和结肠损伤减少。这种变化与结肠和肠系膜炎症的显著减少、已解决的肠系膜淋巴管扩张以及类似于健康对照的 CD103 DC 迁移相关。然而，PMXB 治疗并没有解决结肠内的炎症或相关的肠系膜淋巴功能障碍，但通过改变 CCL21 梯度和 CD103 DC 迁移，确实防止了 MLN 中的淋巴结病。TLR4 似乎介导了肠系膜淋巴管中的几种变化，更具体地说，无论是通过病原体衍生的因子（如 LPS）还是组织衍生的 DAMPs 刺激，它都表现出不同的结果，这是一种新现象。
