Scavenger Receptor A Is a Major Homeostatic Regulator that Restrains Drug-Induced Liver Injury

Research from Dr. Xiang-Yang Wang’s laboratory identified a novel hepatocyte-extrinsic pathway governed by scavenger receptor A (SRA), an immune pattern recognition receptor that maintains liver homeostasis upon drug insult. Considering the fact that acetaminophen (APAP) overdose is the leading cause of acute liver failure, targeting this hepatoprotective mechanism may provide a new immune-based approach to optimize the current management of drug-induced liver injury (DILI).

• Using drug (e.g., APAP)-induced liver injury models, the investigators demonstrated that SRA loss renders mice highly susceptible to drug hepatotoxicity.

• Hepatoprotective activity of SRA was mainly driven by its activity in hepatic myeloid cells (i.e., Kupffer cells, KCs) upon sensing stressed hepatocytes as well as functional regulation of interleukin-10 (IL-10) production from KCs.

• The SRA-IL-10 axis represents a new immune checkpoint circuit that modulates the immunopathogenesis of drug hepatotoxicity that has broad therapeutic implications.

Multiple drugs, both prescription and over-the-counter, can cause hepatotoxicity through a variety of mechanisms. APAP, a widely used over-the-counter analgesic also seen in prescription narcotics or painkillers, is one of the leading causes of drug-induced liver injury. N-acetylcysteine (NAC) is the only approved drug to treat APAP overdose through replenishing glutathione stores. Unfortunately, the benefit of NAC administration decreases with the time elapsed between overdose and treatment. Therefore, there is an unmet medical need to develop alternative or more efficacious treatment options in the clinic. New research from Dr. Xiang-Yang Wang and colleagues demonstrated the biological significance of the immune receptor SRA in antagonizing drug-induced hepatic stress by facilitating KCs to produce the anti-inflammatory and hepatoprotective cytokine IL-10.

SRA, also called CD204, is a pattern recognition receptor primarily expressed on the cells of myeloid origin, e.g., macrophages. Dr. Wang’s research group previously uncovered an immunosuppressive activity of SRA that can abrogate T cell-dependent adaptive antitumor immunity. While APAP-induced liver injury is caused by the direct hepatotoxic effects derived from APAP metabolic activation in hepatocytes, recent studies suggest that APAP hepatotoxicity can be defined by the interplay of hepatocytes with immune cells. A better understanding of the underlying immunologic basis may lead to the discovery of new drug targets for more effective disease intervention. In the present study, the investigators found that lack of SRA rendered mice highly susceptible to APAP overdose, indicated by sharply increased mortality and hepatic injury (Fig. 2A and B) as well as significantly elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities (Fig. 2C). Loss of SRA resulted in profoundly increased liver infiltration of neutrophils (Fig. 2D), which are known to amplify liver injury triggered by APAP. This enhanced hepatotoxicity correlated with marked elevation in hepatic levels of pro-inflammatory and pathogenic cytokine (i.e., IL-17A) as well as impaired production of hepatic IL-10 in SRA^-/- mice (Fig. 2E). The subsequent studies showed that IL-10 as a potent anti-inflammatory cytokine can function down stream of SRA activity and limit hepatic inflammation and injury. The team further demonstrated that combined use of NAC and IL-10 resulted in significantly improved liver protection compared to NAC alone (Fig. 2F), indicating that targeting the SRA-IL-10 immune pathways may complement NAC treatment for additional benefits or extend the therapeutic window of NAC.

Drs. Chunqing Guo, Wenjie Liu and Zheng Liu from the Department of Human and Molecular Genetics (HMG) at Virginia Commonwealth University, School of Medicine are the lead authors of this paper. The present study was supported in part by Veterans Affairs (VA) Merit Award 1I01BX003275 and Department of Defense Medical Research Award W81XWH1910538. VCU Flow cytometry facility was supported in part by NCI Cancer Center Support Grant to VCU Massey Cancer Center P30CA16059.

Publications:

Guo C^#, Liu W^#, Liu Z^#, Cai J, Yu X, Wang H, Li X, Zuo D, Jiang X, Zhang B, Liu J, Sanyal AJ, Puri P, Zhou H, Wang XY. Scavenger receptor a is a major homeostatic regulator that restrains drug-induced liver injury. Hepatology. 2023: Jul 1;78(1):45-57. (^#, equal contribution).

DOI: 10.1097/HEP.0000000000000044

About the Investigators: Xiang-Yang Wang, PhD, is Harry and Judy Wason Distinguished Professor in the Department of HMG; Associate Scientific Director of Immunology, VCU Institute of Molecular Medicine; and co-leader of Developmental Therapeutics Program, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA. Chunqing Guo, PhD, is the co-corresponding author and Assistant Professor in the Department of HMG. Dr. Wenjie Liu is a post-doctoral fellow in the Department of HMG. Dr. Zheng Liu is an Instructor in the Department of HMG.