Thank you for sharing! 🦠🧫👩‍🔬

In regards to your question about reinforcing HS on Tregs, we perhaps could engineer a mouse which overexpresses some of the HS biosynthesis enzymes specifically in Tregs. I would be interested to see whether this would be sufficient to overcome the effects of the psoriasis-induced shedding 🤔

… surface of specific immune cells, but the challenge would be to find an antigen that was expressed on our pro-inflammatory cells but not Tregs (that also isn’t too much of a sledgehammer!)

Hi Brett, thanks for your question!
I would love to try those experiments! We’re currently pretty limited in the tools we have for selectively targeting glycans on specific cell types. It would be cool to engineer some kind of enzyme-antibody conjugate which could selectively break down HS on the…

A huge thank you to my PhD supervisors @douglaspdyer.bsky.social and Amy for their support in this work, as well as our collaborators, including Olga Zubkova and Max Nobis, who made this possible! 💪

Putting all of this together, we propose that immune cells have a heparan sulfate glycocaylx which must be shed to enable migration into tissues. A whole new mechanism regulating immune cell migration!

To confirm that HS on the immune cell surface was regulating migration, we enzymatically cleaved HS from the immune cell surface, which resulted in a greater ability to adhere to endothelial cells and migrate towards the chemokine CCL7

Despite seeing reduced shed and migration in response to the mimetic, in another twist, this actually resulted in greater inflammation due to lower numbers of Tregs 🫣

We next hypothesised that a heparan sulfate mimetic would block cleavage of HS from immune cells and reduce migration and inflammation in this model ⬇️

Immune cells also contained intracellular stores of an enzyme called heparanase, which breaks down heparan sulfate

It turned out that lots of immune cells have HS on their surfaces and they seemed to get rid of it in response to inflammation. We think this process helps them more easily enter the tissues during inflammation

In a major twist, we found that it was actually HS on the immune cells themselves which was reduced following inflammation.

🕵️ What we actually found: We were surprised when we looked directly at the HS on the surface of endothelial cells, and saw no evidence of the presumed shedding of HS from the blood vessel wall

🤔 What we thought: We wanted to see whether this would happen in a model of an inflammatory skin disease called psoriasis, where we had observed that there were elevated levels of a glycan known as heparan sulfate (HS) circulating in the blood

Others have observed that in different inflammatory conditions, the glycocalyx lining our blood vessels is broken down or shed, and this allows more immune cells to enter the tissues and cause inflammation