Intestinal Epithelial Chemokine (C-C Motif) Ligand 7 Overexpression Enhances Acetaminophen-Induced Hepatotoxicity in Mice

Mengwei Niu; Zhihong Luo; Shenhai Gong; Sanda Win; Neil Kaplowitz; Yong Jiang; Peng Chen

doi:10.1016/j.ajpath.2019.09.009

Intestinal Epithelial Chemokine (C-C Motif) Ligand 7 Overexpression Enhances Acetaminophen-Induced Hepatotoxicity in Mice

Am J Pathol. 2020 Jan;190(1):57-67. doi: 10.1016/j.ajpath.2019.09.009. Epub 2019 Oct 11.

Authors

Mengwei Niu¹, Zhihong Luo¹, Shenhai Gong¹, Sanda Win², Neil Kaplowitz², Yong Jiang³, Peng Chen⁴

Affiliations

¹ Department of Pathophysiology, School of Basic Medical Sciences, Guangdong Provincial Key Laboratory of Proteomics, Southern Medical University, Guangzhou, China; State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China.
² University of Southern California Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles.
³ Department of Pathophysiology, School of Basic Medical Sciences, Guangdong Provincial Key Laboratory of Proteomics, Southern Medical University, Guangzhou, China; State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China. Electronic address: [email protected].
⁴ Department of Pathophysiology, School of Basic Medical Sciences, Guangdong Provincial Key Laboratory of Proteomics, Southern Medical University, Guangzhou, China; State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China; Microbiome Medicine Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China. Electronic address: [email protected].

Abstract

Acetaminophen (APAP) overdose-induced hepatotoxicity is the leading cause of drug-induced liver injury worldwide. The related injury pathogenesis is mainly focused on the liver. Here, the authors report that gut barrier disruption may also be involved in APAP hepatotoxicity. APAP administration led to gut leakiness and colonic epithelial chemokine (C-C motif) ligand 7 (CCL7) up-regulation. Intestinal epithelial cell (IEC)-specific CCL7 transgenic mice (CCL7^tgIEC mice) showed markedly increased myosin light chain kinase phosphorylation, and elevated gut permeability and bacterial translocation into the liver compared to wild-type mice. Global transcriptome analysis revealed that the expression of hepatic proinflammatory genes was enhanced in CCL7^tgIEC mice compared with wild-type animals. Moreover, CCL7 overexpression in intestinal epithelial cells significantly augmented APAP-induced acute liver injury. These data provide new evidence that dysfunction of CCL7-mediated gut barrier integrity may be an important contributor to APAP-induced hepatotoxicity.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acetaminophen / toxicity*
Analgesics, Non-Narcotic / toxicity*
Animals
Bacterial Translocation
Cell Membrane Permeability
Chemical and Drug Induced Liver Injury / etiology
Chemical and Drug Induced Liver Injury / metabolism
Chemical and Drug Induced Liver Injury / pathology*
Chemokine CCL7 / genetics
Chemokine CCL7 / metabolism*
Epithelial Cells / metabolism
Epithelial Cells / pathology*
Gene Expression Profiling
Gene Expression Regulation*
Intestines / physiopathology*
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic

Substances

Analgesics, Non-Narcotic
Ccl7 protein, mouse
Chemokine CCL7
Acetaminophen

Abstract

Publication types

MeSH terms

Substances

Grants and funding