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Platelet Hyaluronidase-2 regulates the early stages of inflammatory disease in colitis

Aaron C. Petrey, Dana R. Obery, Sean P. Kessler Ph.D., Ash Zawerton, Bruno Flamion and Carol A. de la Motte

Key Points

  • Hyaluronan catabolism is dysregulated in IBD patient endothelium

  • Platelet HYAL2 regulates inflammation by limiting leukocyte trans-endothelial migration

Abstract

Platelets are specialized cells essential for hemostasis that also function as crucial effectors capable of mediating inflammatory and immune responses. These sentinels continually survey their environment and discriminate between homeostatic and danger signals, such as modified components of the extracellular matrix (ECM). The glycosaminoglycan hyaluronan (HA) is a major ECM component coating the vascular lumen and under normal conditions restricts access of inflammatory cells. In response to tissue damage, the endothelial HA matrix enhances leukocyte recruitment and regulates the early stages of the inflammatory response. We have demonstrated that platelets can degrade HA from the surface of activated endothelial cells via the enzyme hyaluronidase-2 (HYAL2), and that HYAL2 is deficient in platelets isolated from inflammatory bowel disease (IBD) patients. Platelets are known to participate in the pathogenesis of several chronic disease states including IBD, but they have been largely overlooked in the context of intestinal inflammation. We therefore wanted to define the mechanism by which platelet HYAL2 regulates the inflammatory response during colitis. In this study we provide evidence that HA catabolism is disrupted in human intestinal microvascular endothelial cells isolated from IBD patients. Further, mice deficient in HYAL2 are more susceptible to an acute model of colitis, and this increased susceptibility is abrogated by transfusion of HYAL2-competent platelets. Finally, we demonstrate that platelets, via HYAL2-dependent degradation of endothelial HA, regulate the early stages of inflammation in colitis by limiting leukocyte extravasation.

  • Submitted December 21, 2018.
  • Revision received June 28, 2019.
  • Accepted June 12, 2019.