In Vivo Characterization and Functional Effects of the NAD+ Transporter, SLCA25A51

Background and aims: Liver inflammation will cause hepatic damage.In other cases, hepatic injury or poisoning will induce inflammation.Both scenarios will be defined as hepatitis.We chose two distinct hepatitis models that are typical for these two underlying causes.By doing so, we aimed to characterize the role of PAR2 in liver regeneration and inflammation, to reconcile PAR2 confusing role in many damage models, which sometimes aggravates the induced damage and sometimes alleviates it.Method: WT and PAR2 knock out (PAR2KO) mice were injected with concanavalin A (ConA) for the immune-mediated model, or with carbon tetrachloride (CCl 4 ) for the direct hepatic damage.In order to separate the immune component from the liver regenerative response we conducted reciprocal bone marrow (BM) replacement of WT and PAR2KO mice and repeated the damage models.Results: ConA injection caused limited damage in PAR2KO mice livers, while in the WT severe damage followed by leukocytes infiltration was evident.Reciprocal BM replacement of WT and PAR2KO showed that WT BM into PAR2KO displayed marked liver damage, while in PAR2KO BM into WT the tissue was generally protected.In the CCl 4 direct damage model, WT mice hepatocytes regenerated, while PAR2KO failed to recover.Reciprocal BM replacement did not show significant difference in hepatic regeneration comparing to the mice that were not transplanted.In PAR2KO hepatitis was significantly more apparent, while WT recovered regardless of the BM origin.Figure: ConA induced hepatitis is controlled by PAR2 activation in the immune systemConclusion: We conclude that when PAR2 is predominantly activated in the immune system, it aggravates hepatitis and when it is activated in the damaged tissue it promotes liver regeneration.When we incorporate this finding and revisit the literature reports, we were able to reconcile the conflicts surrounding PAR2 role in injury, recovery, and inflammation.