NLRX1 as a novel therapeutic target: TRAF6-dependent inhibition of acute rejection in rat liver transplantation.

Abstract

Recent research has underscored NLRX1's role in modulating hepatic immune responses. However, its function in Kupffer cells (KCs) during acute rejection (AR) post-liver transplantation is not well elucidated, and the mechanisms driving hepatic AR require deeper investigation. Our study found that NLRX1 expression was markedly reduced in hepatic AR models, both in vivo and in vitro. NLRX1 overexpression significantly dampened the activation of the MAPK and IKK pathways, leading to decreased cytokine secretion and mitigated liver damage and apoptosis. In contrast, NLRX1 downregulation intensified these adverse effects. Further mechanistic studies indicated that NLRX1's interaction with TRAF6 was crucial for its anti-inflammatory effects, which could be nullified by TRAF6 blockade. Moreover, in vitro assays showed that NLRX1 could drive KCs to transition from a pro-inflammatory M1 to an anti-inflammatory M2 phenotype via the PI3K/Akt pathway. Overall, our results imply that targeting NLRX1 in conjunction with mTOR could be a viable approach to prevent hepatic AR, and suggest potential cross-talk between TRAF6-dependent inflammatory suppression and PI3K/Akt-mediated M2 polarization that requires further validation.