Liraglutide Attenuates Hepatic Ischemia-Reperfusion Injury by Modulating Macrophage Polarization

Shang-Lin Li; Zhi-Min Wang; Cong Xu; Fu-Heng Che; Xiao-Fan Hu; Rui Cao; Ya-Nan Xie; Yang Qiu; Hui-Bo Shi; Bin Liu; Chen Dai; Jun Yang

doi:10.3389/fimmu.2022.869050

Liraglutide Attenuates Hepatic Ischemia-Reperfusion Injury by Modulating Macrophage Polarization

Front Immunol. 2022 Apr 5:13:869050. doi: 10.3389/fimmu.2022.869050. eCollection 2022.

Authors

Shang-Lin Li^{1

2}, Zhi-Min Wang³, Cong Xu^{1

2}, Fu-Heng Che^{1

2}, Xiao-Fan Hu^{1

2}, Rui Cao^{1

2}, Ya-Nan Xie^{1

2}, Yang Qiu^{1

2}, Hui-Bo Shi^{1

2}, Bin Liu^{1

2}, Chen Dai^{1

2}, Jun Yang^{1

2}

Affiliations

¹ Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
² Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
³ Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Abstract

Ischemia-reperfusion injury (IRI) is a common complication associated with liver surgery, and macrophages play an important role in hepatic IRI. Liraglutide, a glucagon-like peptide-1 (GLP-1) analog primarily used to treat type 2 diabetes and obesity, regulates intracellular calcium homeostasis and protects the cardiomyocytes from injury; however, its role in hepatic IRI is not yet fully understood. This study aimed to investigate whether liraglutide can protect the liver from IRI and determine the possible underlying mechanisms. Our results showed that liraglutide pretreatment significantly alleviated the liver damage caused by ischemia-reperfusion (I/R), as evidenced by H&E staining, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, and TUNEL staining. Furthermore, the levels of inflammatory cytokines elicited by I/R were distinctly suppressed by liraglutide pretreatment, accompanied by significant reduction in TNF-α, IL-1β, and IL-6 levels. Furthermore, pretreatment with liraglutide markedly inhibited macrophage type I (M1) polarization during hepatic IRI, as revealed by the significant reduction in CD68⁺ levels in Kupffer cells (KCs) detected via flow cytometry. However, the protective effects of liraglutide on hepatic IRI were partly diminished in GLP-1 receptor-knockout (GLP-1R^-/-) mice. Furthermore, in an in vitro study, we assessed the role of liraglutide in macrophage polarization by examining the expression profiles of M1 in bone marrow-derived macrophages (BMDMs) from GLP-1R^-/- and C57BL/6J mice. Consistent with the results of the in vivo study, liraglutide treatment attenuated the LPS-induced M1 polarization and reduced the expression of M1 markers. However, the inhibitory effect of liraglutide on LPS-induced M1 polarization was largely abolished in BMDMs from GLP-1R^-/- mice. Collectively, our study indicates that liraglutide can ameliorate hepatic IRI by inhibiting macrophage polarization towards an inflammatory phenotype via GLP-1R. Its protective effect against liver IRI suggests that liraglutide may serve as a potential drug for the clinical treatment of liver IRI.

Keywords: acute liver injury; glucagon-like peptide-1 receptor; ischemia-reperfusion; liraglutide; macrophage polarization.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Diabetes Mellitus, Type 2* / drug therapy
Lipopolysaccharides / pharmacology
Liraglutide / pharmacology
Liraglutide / therapeutic use
Liver / metabolism
Macrophages / metabolism
Mice
Mice, Inbred C57BL
Reperfusion Injury* / metabolism

Substances

Lipopolysaccharides
Liraglutide