SS‐31 Protects Liver from Ischemia‐Reperfusion Injury via Modulating Macrophage Polarization

Shang, Longcheng; Ren, Haozhen; Wang, Shuai; Liu, Hanyi; Hu, Anyin; Gou, Peng; Lin, Yunzhen; Zhou, Jingchao; Zhu, Wei; Shi, Xiaolei

doi:10.1155/2021/6662156

Cited by 28 publications

(18 citation statements)

References 56 publications

(60 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Harvested liver tissues were fixed in 4% formalin and embedded in paraffin blocks. Four-micrometer sections were stained with hematoxylin and eosin (H&E), and liver damage caused by I/R was scored by a pathologist blindly using Suzuki criteria ( 18 ) on a scale from 0–4.…”

Section: Methodsmentioning

confidence: 99%

Liraglutide Attenuates Hepatic Ischemia–Reperfusion Injury by Modulating Macrophage Polarization

Wang

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

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.

show abstract

Section: Methodsmentioning

confidence: 99%

Liraglutide Attenuates Hepatic Ischemia–Reperfusion Injury by Modulating Macrophage Polarization

Wang

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…The hepatic warm IRI model was described previously with slight modifications [ 20 ]. In brief, isoflurane in combination with chloral hydrate was used for anesthesia, and the portal vein and arterial blood supply to the left and median liver lobes were blocked using an atraumatic clip.…”

Section: Methodsmentioning

confidence: 99%

Antibiotic pretreatment attenuates liver ischemia–reperfusion injury by Farnesoid X receptor activation

et al. 2022

Self Cite

View full text Add to dashboard Cite

Prophylactic antibiotics (Abx) are used before liver surgery, and the influence of antibiotic pretreatment on hepatic ischemia–reperfusion injury (IRI) remains unclear. Hence, we explored the impact of Abx pretreatment on hepatic IRI in the present work. The gut microbiota has an essential role in hepatic bile acid (BA) metabolism, and we assumed that depletion of the gut microbiota could affect the composition of hepatic BAs and affect liver IRI. The IRI model demonstrated that Abx pretreatment attenuated liver IRI by alleviating cell apoptosis, reducing the inflammatory response, and decreasing the recruitment of CCR2+ monocytes. Mechanistically, Abx pretreatment reshaped the gut microbiota, especially decreasing the relative abundance of Firmicutes and increasing the relative abundance of Clostridium, which were related to the transformation of BAs and were consistent with the altered bile acid species (unconjugated BAs, especially UDCA). These altered BAs are known FXR agonists and lead to the activation of the farnesoid X receptor (FXR), which can directly bind to the FXR response element (FXRE) harbored in the TLR4 promoter and further suppress downstream mitogen-activated protein kinase (MAPK) and nuclear kappa B (NF-κB) pathways. Meanwhile, the CCL2–CCR2 axis was also involved in the process of FXR activation, as we confirmed both in vivo and in vitro. Importantly, we proved the importance of FXR in mice and clinical occlusion samples, which were inversely correlated with liver injury. Taken together, our study identified that Abx pretreatment before liver resection was a beneficial event by activating FXR, which might become a potential therapeutic target in treating liver injury.

show abstract

“…A previous study has demonstrated that SS-31, a mitochondrial-targeted antioxidant peptide, directly decreases ROS production and regulates signal transducer and activator of transcription 1/3 (STAT1/STAT3) signaling in macrophages, causing M2 polarization phenotype. The peptide also decreased the production of proinflammation cytokines, thereby mitigating inflammatory response in the liver [ 81 ].…”

Section: Hepatic Microenvironmentmentioning

confidence: 99%

Targeting the Hepatic Microenvironment to Improve Ischemia/Reperfusion Injury: New Insights into the Immune and Metabolic Compartments

Gao¹,

Qiu²,

Wang³

et al. 2022

Aging and disease

View full text Add to dashboard Cite

Hepatic ischemia/reperfusion injury (IRI) is mainly characterized by high activation of immune inflammatory responses and metabolic responses. Understanding the molecular and metabolic mechanisms underlying development of hepatic IRI is critical for developing effective therapies for hepatic IRI. Recent advances in research have improved our understanding of the pathogenesis of IRI. During IRI, hepatocyte injury and inflammatory responses are mediated by crosstalk between the immune cells and metabolic components. This crosstalk can be targeted to treat or reverse hepatic IRI. Thus, a deep understanding of hepatic microenvironment, especially the immune and metabolic responses, can reveal new therapeutic opportunities for hepatic IRI. In this review, we describe important cells in the liver microenvironment (especially non-parenchymal cells) that regulate immune inflammatory responses. The role of metabolic components in the diagnosis and prevention of hepatic IRI are discussed. Furthermore, recent updated therapeutic strategies based on the hepatic microenvironment, including immune cells and metabolic components, are highlighted.

show abstract

SS‐31 Protects Liver from Ischemia‐Reperfusion Injury via Modulating Macrophage Polarization

Cited by 28 publications

References 56 publications

Liraglutide Attenuates Hepatic Ischemia–Reperfusion Injury by Modulating Macrophage Polarization

Liraglutide Attenuates Hepatic Ischemia–Reperfusion Injury by Modulating Macrophage Polarization

Antibiotic pretreatment attenuates liver ischemia–reperfusion injury by Farnesoid X receptor activation

Targeting the Hepatic Microenvironment to Improve Ischemia/Reperfusion Injury: New Insights into the Immune and Metabolic Compartments

Contact Info

Product

Resources

About