During Inflammatory Bowel Disease (IBD), the large molecule hyaluronan (HA) on the surface of epithelial forms long branches that reach out into the surrounding environment. This branched HA acts as a landing site for incoming immune cells. When one is healthy, however, this branched HA (HC:HA) needs to be cut back. This process is called “HA metabolism,” and it is lost during IBD. When the pro-inflammatory branches should be cut back to the protective form of HA, patients instead maintain those recruiting branches. Therefore, we sought to examine what could be driving this biological disfunction, looking first at the enzyme that cuts HA, hyaluronidase-2 (HYAL-2).

Two groups of mice underwent experimental IBD: normal, wild type mice, and then HYAL-2 knockout mice, which are mice that have the enzyme necessary for cleaving HA (hyaluronidase-2) deleted. After 7 days, the HYAL-2 knockout mice were significantly sicker compared to the wild type mice. While this confirmed that losing the ability to cleave HA made worsened symptoms during IBD, it did not answer what cells were driving this reduction of HA metabolism in patients.

We choose to examine platelets, as the tiny cells are known to be abnormal during IBD, leading to higher number of clots in patients. Platelets from mice undergoing IBD in the laboratory have shown a reduced ability to cleave HA when compared to healthy platelets. We further examined this abnormal platelet behavior, finding that colitis led to platelets with lower hylurodinase-2 protein levels and reduced capability of cleaving HA. Signs were pointing to platelets as one of the major culprits of HA metabolism dysregulation during IBD.

But all of our experiments had been in mice with HYAL-2 completely deleted everywhere in the mouse’s body. To determine whether platelets drove HA cleaving during IBD, we needed to knock out HYAL-2 in only platelets. We performed an experiment where we replaced the platelets of our normal mice with those of a HAYL-2 KO mouse, and vice versa. Wild type mice with the HYAL-2 KO platelets had worsened disease symptoms during experimental colitis. Inversely, injecting a HYAL-2 KO mouse with normal mouse platelets throughout the disease improved symptoms. Our findings excited us, as we’d found not only a convincing explanation for the dysregulation of HA metabolism in IBD, but we also found that reviving platelet HYAL-2 function improved IBD symptoms in mice.