Mo1824 miR-511-3p, Embedded in the Macrophage Mannose Receptor Gene, Contributes to Experimental Colitis

Abstract

Approximately 40% of inflammatory bowel diseases (IBD) are associated with thromboembolic events causing significant rate of morbidity and mortality. These extra intestinal events of IBD are initiated by the qualitative and quantitative abnormalities in both coagulation and fibrinolytic factors producing states of hypercoagulability. Nevertheless, the interrelationship between IBD pathogenesis and hypercoagulability condition is not well understood (Figure 1). Here we examine the role of a coagulable state triggered by impaired fibrinolysis in the development of chronic colonic inflammation. Plasminogen (Plg) is the primary fibrinolytic enzyme, becomes activated to serine protease plasmin to dissolve the fibrin clot and to counterbalance hypercoagulability. The rapidity of IBD is caused by combining the effects of genetic and environmental factors. Our data show that when fed with a high fat diet (HFD, 45% milk fat), mouse knockout of Plg (Plg-/mice) developed continuous lesions in the colon with multiple inflammatory polyps (as of 8 weeks, n=15) bearing ulcers. This pathophysiology was not observed in HFD fed wild type (Plg+/+) mice and standard chow diet fed Plg+/+ and Plg-/mice. The increased inflammatory cell infiltration in the colon of HFD fed Plg-/mice was corroborated with increased levels of pro-inflammatory cytokines (IL-6, IL-17 & TNF alpha). In addition, HFD-fed Plg-/mice expressed reduced levels of colonic epithelial tight junctions (Claudin1, Occludin and ZO1), a finding compatible with an impaired epithelial barrier function, compared to Plg+/+ mice. Moreover, HFD fed Plg-/mice showed increased levels of plasma endotoxin, an indicator of impaired intestinal barrier function, compared with HFD-fed Plg+/+ mice. All these pathologies of HFD fed Plg-/mice were associated with excessive fibrin deposition in both vascular and extravascular space in the colon compared with HFD fed Plg+/+ mice providing a link between fibrin deposition and inflammation. Altogether, our present data imply that fibrinolytic pathway plays a crucial role in colon homeostasis and defects in this pathway can cause impaired colon barrier function and sustained colonic inflammation. In depth exploration of this pathway will provide a clue towards the potential role of Plg in colon homeostasis. This study will also challenge current paradigms on the relationship between coagulation abnormalities and IBD, which presume that these abnormalities are a consequence rather than a cause of the disease.