Solving PAR2`s role in different hepatic disease models

The G-protein coupled receptor, Protease activated receptor 2 (PAR2) has a pivotal role in various models of injury, inflammation and regeneration. However, while PAR2’s activity is always significant in its function, its role is puzzling, sometimes aggravating the disease phenotype, while sometimes alleviating it. As a result, the literature is riddled with anecdotal reports of PAR2’s role in different injury and disease models.

Trying to understand PAR2’s function in tissue regeneration and inflammation, we aimed to compare autoimmune hepatitis to direct hepatic damage model. WT and PAR2 knock out mice were injected with Concanavalin A for the (auto)immune model, or with carbon tetrachloride for the direct hepatic damage. Using bone marrow replacement experiments, we described that PAR2 activation in leukocytes is required for efficient immune response, and in the damaged tissue, it is required for regeneration of the damaged cells. Thus, PAR2 function in alleviating or aggravating the disease phenotype is determined by the interplay between two major factors: the immune system and the affected tissue, depending on the dominance of the one that is more significant in the damage model selected. We conclude that when PAR2 is activated in the immune system, it aggravates inflammation and when it is activated in the damaged tissue, it promotes regeneration.

We summarize PAR2’s confusing role below:

If the damage is propagated by inflammation ==> PAR2 activation will aggravate it.

If the damage is mediated by direct tissue injury ==> PAR2 activation will induce regeneration.