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

Abstract

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.

Par2-mediated responses in inflammation and regeneration: choosing between repair and damage

“…Furthermore, a study combining ApoE deletion with BM replacement experiments demonstrated that Par2KO mice exhibited a decreased atherosclerotic phenotype compared to control mice [ 88 ]. This study indicated that the atherosclerotic phenotype is mediated by Par2 activation in the immune system, which aligns with our recent work demonstrating the role of leukocyte Par2 in ConA-induced hepatitis [ 23 ].…”

“…In the ConA model, we demonstrated that when Par2 was expressed in the immune system, the inflammatory response was intensified, as shown by Song et al and Li et al However, when Par2 was expressed in the tissue and not in the immune cells, the livers were protected from the damage induced by ConA. However, when we attempted to replicate these findings in the CCl 4 model, we found that immune cell Par2 did not affect the damage, and liver recovery was completely dependent on Par2 expression in hepatocytes [ 23 ]. These observations led us to the conclusion that Par2 has two roles: in leukocytes, it promotes an inflammatory response, and in the target tissue, it promotes regeneration.…”

“…Our investigations into Par2 activation have revealed intriguing observations in models of liver damage. When exposed to concanavalin A (ConA) poisoning, Par2 led to significant hepatitis with marked leukocyte infiltrations, while Par2 knockout (Par2KO) mice showed protection against liver damage without infiltrates [ 23 ]. Surprisingly, when carbon tetrachloride (CCl 4 ) replaced ConA, we noticed the exact opposite phenotype: wild-type (WT) mice exhibited rapid recovery from liver damage, whereas Par2KO mice failed to heal.…”

“…Embryonic development is often associated with regenerative processes, raising the expectation that Par2KO animals may exhibit impaired embryonic development. However, no developmental delays were observed in Par2KO pups [ 12 , 23 ]. Nevertheless, examination of embryos at E13.5 and 18.5 revealed reduced fetal and placental weights [ 127 ].…”