TY - JOUR
T1 - Platelet hyaluronidase-2 regulates the early stages of inflammatory disease in colitis
AU - Petrey, Aaron C.
AU - Obery, Dana R.
AU - Kessler, Sean P.
AU - Zawerton, Ash
AU - Flamion, Bruno
AU - de la Motte, Carol A.
N1 - © 2019 by The American Society of Hematology.
PY - 2019/8/29
Y1 - 2019/8/29
N2 - 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. The glycosaminoglycan hyaluronan (HA) is a major extracellular matrix component that coats 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 shown 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 patients with inflammatory bowel disease (IBD). Platelets are known to be involved 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 patients with IBD. Furthermore, 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 show that platelets, via HYAL2-dependent degradation of endothelial HA, regulate the early stages of inflammation in colitis by limiting leukocyte extravasation.
AB - 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. The glycosaminoglycan hyaluronan (HA) is a major extracellular matrix component that coats 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 shown 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 patients with inflammatory bowel disease (IBD). Platelets are known to be involved 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 patients with IBD. Furthermore, 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 show that platelets, via HYAL2-dependent degradation of endothelial HA, regulate the early stages of inflammation in colitis by limiting leukocyte extravasation.
KW - Animals
KW - Blood Platelets/immunology
KW - Cells, Cultured
KW - Colitis/immunology
KW - Endothelial Cells/immunology
KW - GPI-Linked Proteins/immunology
KW - Humans
KW - Hyaluronic Acid/immunology
KW - Hyaluronoglucosaminidase/immunology
KW - Inflammation/immunology
KW - Inflammatory Bowel Diseases/immunology
KW - Mice
KW - Mice, Knockout
UR - http://www.scopus.com/inward/record.url?scp=85071646478&partnerID=8YFLogxK
U2 - 10.1182/blood.2018893594
DO - 10.1182/blood.2018893594
M3 - Article
C2 - 31262781
AN - SCOPUS:85071646478
SN - 0006-4971
VL - 134
SP - 765
EP - 775
JO - Blood
JF - Blood
IS - 9
ER -