Layilin as a modulator of platelet activation and thromboinflammation

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Abstract Inflammatory Bowel Disease (IBD) is characterized by inappropriate immune cell infiltration within the colon and incidence of this disease grows annually. With currently no cure, patients can only mitigate symptoms through surgery and immunosuppressants. An extracellular matrix component, hyaluronan (HA), is synthesized into cable-like structures during inflammation that act as attachment sites for recruited leukocytes. Platelets bind to these cables and degrade the HA and this capability to metabolize HA is lost during IBD. These HA fragments have pro-inflammatory effects when released into circulation. How platelets recognize HA, however, is unknown. Our long-term goal is to determine a potential drug target for non-invasive treatment in IBD patients by targeting HA receptors on platelets. We have previously found that, contrary to what would be expected, the predominant HA receptor on platelets is not CD44, but the understudied receptor, layilin. The objective of this proposal is to utilize both human IBD patients and murine platelets to determine the role of the hyaluronan receptor, layilin, in platelets. This receptor is downregulated in IBD patients, correlating to the well-documented platelet dysfunction in patients. Preliminary results show that inhibiting this receptor results in loss of platelet aggregation, spreading, and HA degradation. The central hypothesis of this proposal is that dysregulation of platelet-driven HA metabolism enhances recruitment and activation of CD44-expressing cells, such as leukocytes, into the intestinal microvasculature. The rationale for this project is that layilin could be a novel target for treatment of platelet dysregulation in chronic inflammatory diseases. It may be acting as a negative regulator for platelet activation based on our preliminary results. The central hypothesis will be tested by examining two specific aims: 1) to determine how layilin mediates cell signaling driving platelet activation and 2) to determine the mechanism by which layilin influences inflammation in a murine model of colitis. This approach is innovative because it targets the understudied receptor in hyperactive platelets, a cell type not extensively investigated in disease progression of IBD. In the final aim, we will also be utilizing platelet specific LAYN KO (PF4-Cre LAYNfl/fl) and WT mice to produce a novel murine model for ulcerative colitis. The proposed research is significant because we anticipate this research to develop a non-invasive treatment for thromboinflammatory diseases.