Acute small intestinal inflammation results in persistent lymphatic alterations

Abstract

Inflammatory bowel disease (IBD) has a complex pathophysiology with limited treatments. Structural and functional changes in the intestinal lymphatic system have been associated with the disease, with increased risk of IBD occurrence linked to a history of acute intestinal injury. To examine the potential role of the lymphatic system in inflammation recurrence, we evaluated morphological and functional changes in mouse mucosal and mesenteric lymphatic vessels, and within the mesenteric lymph nodes during acute ileitis caused by a 7-day treatment with dextran sodium sulfate (DSS). We monitored whether the changes persisted during a 14-day recovery period and determined their potential consequences on dendritic cell (DC) trafficking between the mucosa and lymphoid tissues. DSS administration was associated with marked lymphatic abnormalities and dysfunctions exemplified by lymphangiectasia and lymphangiogenesis in the ileal mucosa and mesentery, increased mesenteric lymphatic vessel leakage, and lymphadenopathy. Lymphangiogenesis and lymphadenopathy were still evident after recovery from intestinal inflammation and correlated with higher numbers of DCs in mucosal and lymphatic tissues. Specifically, a deficit in CD103 DCs observed during acute DSS in the lamina propria was reversed and further enhanced during recovery. We concluded that an acute intestinal insult caused alterations of the mesenteric lymphatic system, including lymphangiogenesis, which persisted after resolution of inflammation. These morphological and functional changes could compromise DC function and movement, increasing susceptibility to further gastrointestinal disease. Elucidation of the changes in mesenteric and intestinal lymphatic function should offer key insights for new therapeutic strategies in gastrointestinal disorders such as IBD. NEW & NOTEWORTHY Lymphatic integrity plays a critical role in small intestinal homeostasis. Acute intestinal insult in a mouse model of acute ileitis causes morphological and functional changes in mesenteric and intestinal lymphatic vessels. While some of the changes significantly regressed during inflammation resolution, others persisted, including lymphangiogenesis and altered dendritic cell function and movement, potentially increasing susceptibility to the recurrence of gastrointestinal inflammation.

Lipopolysaccharides modulate intestinal epithelial permeability and inflammation in a species-specific manner

“…A disruption of the mesenteric lymphatic system is a well-documented sign of intestinal inflammation in two animal models of human IBD. 51,52 Whether the disruption in effective lymph flow is driven by the translocated bacteria is still to be validated. However, evidence points to it as being a key component.…”

Mesenteric Lymphatic Alterations Observed During DSS Induced Intestinal Inflammation Are Driven in a TLR4-PAMP/DAMP Discriminative Manner

“…During the progression of IBD extra-cellular matrix remodeling is common, the role of this remodeling however, is poorly understood and it is thought that extracellular molecules produced during this destructive/reparative stage may in fact perpetuate inflammation (53). We have previously demonstrated that even after the removal of DSS, remodeled lymphatics persist, a phenomenon that is evident with the IBD patient population (3).…”

“…The promotion of lymphangiogenesis within the mesentery of DSS treated animals is a well-documented phenomenon (3, 10). Alongside lymphangiogenesis, vessel dilation mediated by iNOS-dependent production of nitric oxide is a common feature associated with inflammation within the tissue surrounding the lymphatics (37).…”

“…Lymphangiectasia, the dilation of lymphatic vessels, is a common sign of collecting lymphatic vessel disruption. It has been shown to be associated in case of inflammation, and intestinal inflammation in particular, with increase permeability of the lymphatics (3, 4). This can result in oedema, hypoproteinaemia, lymphocytopenia, and immunologic anomalies.…”

Blood and Lymphatic Vasculatures On-Chip Platforms and Their Applications for Organ-Specific In Vitro Modeling

“…However, whether the increased vessel densities resolve or sustain the IBD is still unclear, these new vasculatures are leaky, which can exacerbate the inflammatory condition. Increased vascular permeability is another key feature during inflammation [99,100]. Additionally, stage-dependent changes in the blood flow have been reported in experimental colitis models.…”