Biosciences Research Seminar - An epithelial damage sensor system decoded; the first intracellular signal of your life?

Almost all stratified epithelia exist in a state of balance, continually turned-over and replaced from a basal stem cell compartment. In addition, most are poised to respond rapidly to external insults or re-establish the barrier upon wounding. The mechanisms maintaining this poised state must permit an immediate, yet robust response.

We have identified a protease and inhibitor system, present in the basal keratinocytes of vertebrates, essential to maintain both epithelial integrity and quiescent inflammation in zebrafish. Upon loss of the inhibitor (or mis-expression of its cognate protease target), keratinocyte stem cells attain a striking migratory phenotype and the epidermis becomes inflamed, hallmarks of a wound response.

The target of this protease is shown to be a protease activated receptor (PAR2), and we have determined the cellular events resulting from dysregulation of this system, including a marked increase in Reactive Oxygen Species, which, along with activation of other critical pathways, initiates inflammation. Intriguingly, the epithelial defects are uncoupled from the inflammatory responses, and we have implicated the MAPK pathway and intracellular lipid signalling in the keratinocyte phenotype.

Finally, we have found an earlier role for PAR2 in zygote activation following fertilisation, highlighting that this system has been deployed in multiple contexts in development and tissue repair.