Browsing by Author "Rehal, Sonia"

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    Dynamic Alterations of the Mesenteric Lymphatic System in Murine Ileitis: Impications for Crohn’s Disease Pathogenesis
    (2017) Rehal, Sonia; von der Weid, Pierre-Yves; MacNaughton, Wallace; Eksteen, Bertus; McCafferty, Donna-Marie
    Inflammatory bowel disease (IBD) remains a challenging disease to treat due to its complex pathophysiology. It encompasses Crohn’s Disease and ulcerative colitis, both characterized by chronic inflammation. Exaggerated inflammatory responses in IBD are thought to be partly mediated by over-reactive immune cells. In particular, dendritic cells (DCs) have been shown to be over-recruited and hyper-responsive in clinical and experimental IBD tissue. DCs require trafficking through mucosal and mesenteric lymphatic vessels to drain into mesenteric lymph nodes (MLNs). Remodeling of these vessels during inflammation could have dire effects on DC effector function and immune responses in the inflamed intestine. Lymphatic vessel plasticity is also an important concept during acute intestinal injury for proper resolution of inflammation. Human and animal studies demonstrate pathological remodeling of mucosal lymphatic changes during IBD, including lymphangiogenesis and lymphatic vessel dilation. However, no studies have addressed the role of mesenteric lymphatic remodeling in replicable models of acute or chronic ileitis. These objectives were investigated using both the acute, dextran sodium sulphate (DSS) mouse model of ileitis and the chronic, transgenic TNFΔARE mouse model of ileitis. Plasticity of this remodeling was further assessed in recovery DSS mice. Our research findings demonstrate that chronic CD-like ileitis in TNFΔARE mouse model displays many lymphatic abnormalities. These include intestinal lymphangiectasia and MLN lymphadenopathy, reminiscent of human CD. TNFΔARE vessels have increased lipid transport, lymphangiogenesis and critically the development of mesenteric tertiary lymphoid organs (TLOs), actively involved in immune modulation; all of which we believe cause altered DC trafficking in these mice. Many of these changes were replicated in the acute DSS ileitis mouse model, albeit at a lesser extent. However, decreased lymph flow was observed during acute injury. Despite having recovered from DSS-induced intestinal inflammation, mice continued to display marked mesenteric lymphatic dysfunctions, such as lymphadenopathy and lymphangiogenesis. Lamina propria (LP), lymphatic vessels and mesenteric lymph nodes (MLNs) also continued to exhibit enhanced DC populations. This study contributes intriguing findings on remodeling of the lymphatic system within the context of small intestinal inflammation, commonly found in CD patients. Modulating lymphatic function during inflammation might offer new therapeutic avenues for IBD.