Resolving the conflicts around Par2 opposing roles in regeneration by comparing immune-mediated and toxic-induced injuries

Gal Reches, Netta R. Blondheim Shraga, Florent Carrette, Assaf Malka, Natalia Saleev, Yehuda Gubbay, Offir Ertracht, Izhak Haviv, Linda M. Bradley, Fred Levine, Ron Piran

Research output: Contribution to journalArticlepeer-review


Background: Different factors may lead to hepatitis. Among which are liver inflammation and poisoning. We chose two hepatitis models, typical for these two underlying causes. Thus, we aimed to characterize the role of protease-activated receptor 2 (Par2) in liver regeneration and inflammation to reconcile Par2 conflicting role in many damage models, which sometimes aggravates the induced damage and sometimes alleviates it. Methods: WT and knockout (Par2KO) mice were injected with concanavalin A (ConA) to induce immune-mediated hepatitis or with carbon tetrachloride (CCl4) to elicit direct hepatic damage. To distinguish the immune component from the liver regenerative response, we conducted bone marrow (BM) replacements of WT and Par2KO mice and repeated the damage models. Results: ConA injection caused limited damage in Par2KO mice livers, while in the WT mice severe damage followed by leukocyte infiltration was evident. Reciprocal BM replacement of WT and Par2KO showed that WT BM-reconstituted Par2KO mice displayed marked liver damage, while in Par2KO BM-reconstituted WT mice, the tissue was generally protected. In the CCl4 direct damage model, hepatocytes regenerated in WT mice, whereas Par2KO mice failed to recover. Reciprocal BM replacement did not show significant differences in hepatic regeneration. In Par2KO mice, hepatitis was more apparent, while WT recovered regardless of the BM origin. Conclusions: We conclude that Par2 activation in the immune system aggravates hepatitis and that Par2 activation in the damaged tissue promotes liver regeneration. When we incorporate this finding and revisit the literature reports, we reconciled the conflicts surrounding Par2’s role in injury, recovery, and inflammation.

Original languageEnglish
Article number52
JournalInflammation and Regeneration
Issue number1
StatePublished - Dec 2022

Bibliographical note

Funding Information:
This work is supported by the Chief Scientist Office in the Israeli Ministry of Health Research #3-15082.

Funding Information:
We thank Dr. Sion Koren and Prof. Jamal Zidan from the Ziv Medical Center for mice irradiation. We thank Dr. Basem Hijazi from the Azrieli Faculty of Medicine for the statistical analysis. We thank Prof. Karl Scorecki for his important advice and suggestions, which promoted this manuscript.

Publisher Copyright:
© 2022, The Author(s).


  • Carbon tetrachloride
  • Concanavalin A
  • Hepatitis
  • Liver regeneration
  • Protease-activated receptor-2 (Par2)


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