# Innate Pattern Recognition Receptor and Acetaminophen-induced Liver Injury

> **NIH VA I01** · VA VETERANS ADMINISTRATION HOSPITAL · 2020 · —

## Abstract

Hepatotoxicity induced by acetaminophen (APAP) has become the leading cause of acute liver failure
among the general and the VA populations. The APAP overdose or abuse causing severe liver injury remains a
great threat to veterans. Currently, the standard of care implemented uses high doses of the L-cysteine precursor
N-Acetylcysteine (NAC) making it the only treatment option for patients that suffer from APAP-induced liver injury
(AILI). Unfortunately, the therapeutic window of NAC administration between overdose and treatment is narrow
leaving many patients with no other recourses. The focus of research in understanding the pathologic
mechanisms of AILI has been always on intracellular changes in hepatocytes. However, emerging evidence
suggests a critical role of sterile inflammation for modifying the outcome of disease progression. Our preliminary
studies showed that ablation of scavenger receptor A (SRA), an innate pattern recognition receptor primarily
expressed on myeloid cells, e.g., Kupffer cells (KCs), exacerbated AILI indicated by sharply increased mortality
and hepatic inflammation. This was associated with markedly reduced production of anti-inflammatory cytokine
IL-10. SRA expression also positively correlates with IL-10 levels in human blood samples after APAP exposure.
SRA-IL-10 pathway regulates a sophisticated inflammatory cascade including activation of unconventional γδ T
cells that are known to aggravate tissue damage. Our central hypothesis is that SRA acts as a master regulator
of hepatic immunity and promotes liver homeostasis in AILI. The objective of this project is to interrogate and
mechanistically understand SRA as a key hepatic immune `checkpoint' that operates in highly integrated immune
processes during AILI. These include KC response to damage-associated molecular patterns released from
injured hepatocytes, modulation of hepatocyte-intrinsic stress signaling, and mobilization of pathogenic
inflammatory cells. Analyses of clinical specimens from APAP overdose patients for immune alterations will also
be performed to validate our findings in animal models. Furthermore, we will test the feasibility of targeting SRA-
regulated immune network to improve NAC treatment of AILI. Successful completion of this research will
advance our understanding of a novel hepatocyte-extrinsic immunologic mechanism of AILI. It is anticipated that
a crucial role of SRA, as a previously unrecognized immune determinant of AILI, will be established for the first
time. Given an increased risk of drug overdose or abuse among veterans, our research is highly significant and
clinically relevant to the healthcare of veterans. Elucidating the key elements and molecular pathways that define
the pathogenesis of AILI not only will help identify risk factors to decrease the incidence of AILI, but also provide
new opportunities to develop novel immune-targeted therapies that benefit the large population of veterans.

## Key facts

- **NIH application ID:** 9815344
- **Project number:** 5I01BX003275-02
- **Recipient organization:** VA VETERANS ADMINISTRATION HOSPITAL
- **Principal Investigator:** Xiang-Yang Shawn Wang
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9815344

## Citation

> US National Institutes of Health, RePORTER application 9815344, Innate Pattern Recognition Receptor and Acetaminophen-induced Liver Injury (5I01BX003275-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9815344. Licensed CC0.

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