PAR2, A master regulator of regeneration in the adult mammal.

The G-protein coupled receptor, Protease activated receptor 2 (PAR2) was found to be required for a variety regenerative models in the adult mouse. The damage models that were tested include general pancreas regeneration, liver regeneration, digit regeneration, and β-cell regeneration. PAR2 knock out (KO) mice failed to regenerate their damaged tissues in all the selected models. This phenomenon is surprising, because PAR2KO mice do not have a developmental phenotype, since their embryonic as well as their postnatal development is identical to their WT littermates.

Inflammatory events are an essential preliminary step in regenerative processes in the adult mammal. Trying to distil PAR2’s role in tissue regeneration and inflammation, we compared two distinct hepatic damage models. Immune-mediated hepatitis and direct hepatic damage that is not induced by inflammation. WT and PAR2KO mice were injected with the ConA lectin for the (auto)-immune damage, or with CCl₄ for direct hepatic damage. Using bone marrow replacement experiments, we created immune-specific PAR2KO in WT and WT-immune system in PAR2KO mice. We found that PAR2 has a dual function. In leukocytes it is required for efficient immune response, and in the damaged tissue, PAR2 is required for regeneration. In normal conditions, PAR2’s role in regeneration and inflammation goes hand-in-hand, but in autoimmune diseases, it could create a vicious cycle. Insights to autoimmune disorders will be presented as well.