AI Article Synopsis

  • Drug-induced liver injury, often caused by drugs like acetaminophen, can be severe, and the study examines how the pattern recognition receptor A (SRA) influences this process through immune interactions.
  • Mice lacking SRA show increased sensitivity to liver damage, which is linked to reduced levels of the protective cytokine IL-10 and heightened liver inflammation.
  • The research suggests that SRA plays a critical role in protecting the liver by promoting IL-10 production in immune cells, pointing to potential new approaches for treating drug-induced liver injuries.

Article Abstract

Background And Aim: Drug-induced liver injury occurs frequently and can be life threatening. Although drug-induced liver injury is mainly caused by the direct drug cytotoxicity, increasing evidence suggests that the interplay between hepatocytes and immune cells can define this pathogenic process. Here, we interrogate the role of the pattern recognition scavenger receptor A (SRA) for regulating hepatic inflammation and drug-induced liver injury.

Approach And Results: Using acetaminophen (APAP) or halothane-induced liver injury models, we showed that SRA loss renders mice highly susceptible to drug hepatotoxicity, indicated by the increased mortality and liver pathology. Mechanistic studies revealed that APAP-induced liver injury exaggerated in the absence of SRA was associated with the decreased anti-inflammatory and prosurvival cytokine IL-10 concomitant with excessive hepatic inflammation. The similar correlation between SRA and IL-10 expression was also seen in human following APAP uptake. Bone marrow reconstitution and liposomal clodronate depletion studies established that the hepatoprotective activity of SRA mostly resized in the immune sentinel KCs. Furthermore, SRA-facilitated IL-10 production by KCs in response to injured hepatocytes mitigated activation of the Jun N-terminal kinase-mediated signaling pathway in hepatocytes. In addition, supplemental use of IL-10 with N -acetylcysteine, only approved treatment of APAP overdose, conferred mice improved protection from APAP-induced liver injury.

Conclusion: We identify a novel hepatocyte-extrinsic pathway governed by the immune receptor SRA that maintains liver homeostasis upon drug insult. Giving that drug (ie, APAP) overdose is the leading cause of acute liver failure, targeting this hepatoprotective SRA-IL-10 axis may provide new opportunities to optimize the current management of drug-induced liver injury.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10410742PMC
http://dx.doi.org/10.1097/HEP.0000000000000044DOI Listing

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