CXCL16 deficiency attenuates acetaminophen-induced hepatotoxicity through decreasing hepatic oxidative stress and inflammation in mice

Abstract

Chemokine C-X-C ligand 16 (CXCL16), a single-pass Type I membrane protein belonging to the CXC chemokine family, is related to the inflammatory response in liver injury. In present study, we investigated the pathophysiological role of CXCL16, a unique membrane-bound chemokine, in acetaminophen (APAP)-induced hepatotoxicity in mice. Mice were injected with APAP, and blood and tissue samples were harvested at different time points. The serum high-mobility group box 1 and CXCL16 levels were quantified by sandwich immunoassays. The liver tissue sections were stained with hematoxylin-eosin or with dihydroethidium staining. The expressions of CXCL16 and other cytokines were examined by real-time polymerase chain reaction. Ly6-B, p-jun N-terminal kinase (p-JNK), and JNK expressions were measured by western blot analysis. Intracellular glutathione, reactive oxygen species, and malondialdehyde levels were also measured. APAP overdose increased hepatic CXCL16 mRNA and serum CXCL16 protein levels. CXCL16-deficient mice exhibited significantly less liver injury and hepatic necrosis, as well as a lower mortality than wild-type (WT) mice in response to APAP-overdose treatment. APAP elevated the production of oxidative stress and decreased mitochondrial respiratory chain activation in WT mice, which was strongly reversed in CXCL16-knockout mice. In addition, CXCL16 deficiency inhibited the neutrophil infiltration and the production of proinflammatory cytokines triggered by APAP-overdose treatment. Our study revealed that CXCL16 is a critical regulator of liver immune response to APAP-induced hepatotoxicity, thus providing a potential strategy for the treatment of drug-induced acute liver failure by targeting CXCL16.

Inflammation-activated CXCL16 pathway contributes to tubulointerstitial injury in mouse diabetic nephropathy

“…neutrophil accumulation [41] . These studies, in accordance with our findings, suggest that the inhibition of the CXCL16 pathway alleviates renal tubular interstitial injury by suppressing inflammatory response.…”

More Than Just a Removal Service: Scavenger Receptors in Leukocyte Trafficking

“…Possibly the best studied role for SR-PSOX in the recruitment of leukocytes is in the context of hepatic inflammation (207), with its endothelial-expressed form known to interact with intrahepatic CXCR6 + immune cells, such as effector T cells (206, 208), natural killer (NK) cells (209, 210) and NKT cells (199). It has recently been shown that genetic deficiency of SR-PSOX in mice inhibits the extent of inflammation in a model of acetaminophen (APAP)-induced acute liver injury (211). In addition, pharmacological intervention with neutralizing antibodies raised against SR-PSOX has shown inflammation-reducing efficacy in preclinical murine models of sepsis-mediated (212, 213) and carbon tetrachloride (CCl 4 )-mediated (207) acute liver injury.…”

Novel Targets in the Immune Microenvironment of the Hepatic Sinusoids for Treating Liver Diseases

“…81 Several preclinical studies targeting VAP-1 have confirmed that inhibition of its enzymatic activity and/or blockade of its adhesive function with therapeutic antibodies reduces leukocyte infiltration in a range of rodent models of inflammatory diseases. 82 Scavenger receptor that binds phosphatidylserine and oxidized lipids (SR-PSOX), which in its soluble form is also known as the chemokine, CXCL16, is expressed by LSEC 35 and is upregulated in both acutely 83,84 and chronically injured liver tissues. 85 CXCL16 is a specific ligand for the chemokine receptor CXCR6, thus enabling its membrane-bound form to interact with intrahepatic CXCR6 þ immune cells, such as effector T cells, 85,86 natural killer (NK) cells, 87,88 and NKT cells.…”

“…35 Genetic deficiency of SR-PSOX has recently been shown to reduce the extent of inflammation and necrosis in a murine model of acetaminophen (APAP)-induced acute liver injury. 83 Additionally, and perhaps more encouragingly, pharmacological intervention with neutralizing antibodies against SR-PSOX has shown efficacy in reducing inflammation in preclinical murine models of sepsis-mediated 84,89 and carbon tetrachloride (CCl 4 )-mediated 90 acute liver injury. Furthermore, Wehr and colleagues were also able to demonstrate the efficacy of SR-PSOX antibody therapy in a commonly used murine model of NASH, showing a reduction in both macrophage infiltration and triglyceride levels.…”