Hepatic recruitment of eosinophils and their protective function during acute liver injury

Xu, Long; Yang, Yang; Wen, Yankai; Jeong, Jong Min; Emontzpohl, Christoph; Atkins, Constance L.; Sun, Zhaoli; Poulsen, Kyle L.; Hall, David R.; Bynon, John S.; Gao, Bin; Lee, William M.; Rule, Jody; Jacobsen, Elizabeth A.; Wang, Hua; Ju, Cynthia

doi:10.1016/j.jhep.2022.02.024

Cited by 43 publications

(48 citation statements)

References 44 publications

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“…Acute liver injury is a challenging clinical problem caused by various etiologies such as drug overdose, virus infection, alcohol abuse, and sepsis, and it is associated with high morbidity and mortality due to the lack of efficient therapies [ 2 ]. LPS/D-Gal-induced fulminant hepatitis, which is mainly mediated by an inflammatory response and characterized by massive hepatic apoptosis, is a widely accepted rodent model for investigating the mechanisms and screening protective agents that are related to acute liver injury [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

“…Acute liver injury is a serious clinical syndrome affecting public health worldwide, and is mainly characterized by the destruction of hepatic microarchitecture, apoptotic hepatocytes, a massive inflammatory response, and impaired liver function [ 1 ]. Numerous factors could be the stimulators of acute liver injury, such as the hepatitis virus, drugs, and ethanol [ 2 ]. At present, there are still few effective therapeutic strategies for the treatment of acute liver injury [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

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Alanyl-Glutamine Protects against Lipopolysaccharide-Induced Liver Injury in Mice via Alleviating Oxidative Stress, Inhibiting Inflammation, and Regulating Autophagy

Ying

Zheng

et al. 2022

Antioxidants

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Acute liver injury is a worldwide problem with a high rate of morbidity and mortality, and effective pharmacological therapies are still urgently needed. Alanyl-glutamine (Ala-Gln), a dipeptide formed from L-alanine and L-glutamine, is known as a protective compound that is involved in various tissue injuries, but there are limited reports regarding the effects of Ala-Gln in acute liver injury. This present study aimed to investigate the protective effects of Ala-Gln in lipopolysaccharide (LPS)-induced acute liver injury in mice, with a focus on inflammatory responses and oxidative stress. The acute liver injury induced using LPS (50 μg/kg) and D-galactosamine (D-Gal) (400 mg/kg) stimulation in mice was significantly attenuated after Ala-Gln treatment (500 and 1500 mg/kg), as evidenced by reduced plasma alanine transaminase (ALT) (p < 0.01, p < 0.001), aspartate transaminase (AST) (p < 0.05, p < 0.001), and lactate dehydrogenase (LDH) (p < 0.01, p < 0.001) levels, and accompanied by improved histopathological changes. In addition, LPS/D-Gal-induced hepatic apoptosis was also alleviated by Ala-Gln administration, as shown by a greatly decreased ratio of TUNEL-positive hepatocytes, from approximately 10% to 2%, and markedly reduced protein levels of cleaved caspase-3 (p < 0.05, p < 0.001) in liver. Moreover, we found that LPS/D-Gal-triggered oxidative stress was suppressed after Ala-Gln treatment, the effect of which might be dependent on the elevation of SOD and GPX activities, and on GSH levels in liver. Interestingly, we observed that Ala-Gln clearly inhibited LPS/D-Gal exposure-induced macrophage accumulation and the production of proinflammatory factors in the liver. Furthermore, Ala-Gln greatly regulated autophagy in the liver in LPS/D-Gal-treated mice. Using RAW264.7 cells, we confirmed the anti-inflammatory role of Ala-Gln-targeting macrophages.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Alanyl-Glutamine Protects against Lipopolysaccharide-Induced Liver Injury in Mice via Alleviating Oxidative Stress, Inhibiting Inflammation, and Regulating Autophagy

Ying

Zheng

et al. 2022

Antioxidants

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“…Furthermore, in addition to chemotaxis, the interactions of chemokines at receptors on mast cells can also lead to their activation and degranulation ( 64 ) and feed-forward production of more chemokines ( 65 ). The other granulocyte mentioned are eosinophils which are associated with parasitic infection and allergic responses, but also have been described to play roles in tissue injury and resolution ( 66 ). Eosinophils express a number of chemokine receptors that will lead to migration towards a site of tissue injury or infection which include CXCR1, CXCR2, CXCR3, CXCR4, as well as CCR1, CCR2, CCR3, CCR6 and CCR8 ( 67 ).…”

Section: Cell Recruitment By Chemokines In Liver Injurymentioning

confidence: 99%

“…Similar to most immune cells, eosinophils are also important sources of chemokines. A recent study showed that eosinophils are protective against chemically-induced fibrosis as well as acute liver injury ( 66 ). The study went on to show that the chemokines responsible for eosinophil chemotaxis were due to CCL24 produced by macrophages in a dynamic crosstalk, further demonstrating how tightly controlled the chemokine system can be in disease and homeostasis ( 66 ).…”

Section: Cell Recruitment By Chemokines In Liver Injurymentioning

confidence: 99%

Role of the chemokine system in liver fibrosis: a narrative review

Poulsen¹,

Ross²,

Chaney³

et al. 2022

Dig Med Res

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Background and Objective: Liver fibrosis is a disease with characteristics of an aberrant wound healing response. Fibrosis is commonly the end-stage for chronic liver diseases like alcohol-associated liver disease (ALD), metabolic-associated liver disease, viral hepatitis, and hepatic autoimmune disease. Innate immunity contributes to the progression of many diseases through multiple mechanisms including production of pro-inflammatory mediators, leukocyte infiltration and tissue injury. Chemokines and their receptors orchestrate accumulation and activation of immune cells in tissues and are associated with multiple liver diseases; however, much less is known about their potential roles in liver fibrosis. This is a narrative review of current knowledge of the relationship of chemokine biology to liver fibrosis with insights into potential future therapeutic opportunities that can be explored in the future. Methods: A comprehensive literature review was performed searching PubMed for relevant English studies and texts regarding chemokine biology, chronic liver disease and liver fibrosis published between 1993 and 2021. The review was written and constructed to detail the intriguing chemokine biology, the relation of chemokines to tissue injury and resolution, and identify areas of discovery for fibrosis treatment. Key Content and Findings: Chemokines are implicated in many chronic liver diseases, regardless of etiology. Most of these diseases will progress to fibrosis without appropriate treatment. The contributions of chemokines to liver disease and fibrosis are diverse and include canonical roles of modulating hepatic inflammation as well as directly contributing to fibrosis via activation of hepatic stellate cells (HSCs). Limited clinical evidence suggests that targeting chemokines in certain liver diseases might provide a therapeutic benefit to patients with hepatic fibrosis. Conclusions: The chemokine system of ligands and receptors is a complex network of inflammatory signals in nearly all diseases. The specific sources of chemokines and cellular targets lend unique pathophysiological consequences to chronic liver diseases and established fibrosis. Although most chemokines are pro-inflammatory and contribute to tissue injury, others likely aid in the resolution of established fibrosis. To date, very few targeted therapies exist for the chemokine system and liver disease and/or fibrosis, and further study could identify viable treatment options to improve outcomes in patients with end-stage liver disease.

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“…These immune cells account for 10–20% of the total number of liver cells [ 31 ].In addition, the liver recruits circulating immune cells including macrophages, neutrophils, eosinophils, T lymphocytes, etc. [ 32 , 33 ]. Immune dysfunction takes responsible to various kinds of liver diseases, including DILI, fatty liver disease, autoimmune liver disease, etc.…”

Section: Role Of Immune Cells In Ailimentioning

confidence: 99%

The immunological mechanisms and therapeutic potential in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity

Chen

Wang

2022

Cell Biosci

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Acute liver failure caused by drug overdose is a significant clinical problem in developed countries. Acetaminophen (APAP), a widely used analgesic and antipyretic drug, but its overdose can cause acute liver failure. In addition to APAP-induced direct hepatotoxicity, the intracellular signaling mechanisms of APAP-induced liver injury (AILI) including metabolic activation, mitochondrial oxidant stress and proinflammatory response further affect progression and severity of AILI. Liver inflammation is a result of multiple interactions of cell death molecules, immune cell-derived cytokines and chemokines, as well as damaged cell-released signals which orchestrate hepatic immune cell infiltration. The immunoregulatory interplay of these inflammatory mediators and switching of immune responses during AILI lead to different fate of liver pathology. Thus, better understanding the complex interplay of immune cell subsets in experimental models and defining their functional involvement in disease progression are essential to identify novel therapeutic targets for the treatment of AILI. Here, this present review aims to systematically elaborate on the underlying immunological mechanisms of AILI, its relevance to immune cells and their effector molecules, and briefly discuss great therapeutic potential based on inflammatory mediators.

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Hepatic recruitment of eosinophils and their protective function during acute liver injury

Cited by 43 publications

References 44 publications

Alanyl-Glutamine Protects against Lipopolysaccharide-Induced Liver Injury in Mice via Alleviating Oxidative Stress, Inhibiting Inflammation, and Regulating Autophagy

Alanyl-Glutamine Protects against Lipopolysaccharide-Induced Liver Injury in Mice via Alleviating Oxidative Stress, Inhibiting Inflammation, and Regulating Autophagy

Role of the chemokine system in liver fibrosis: a narrative review

The immunological mechanisms and therapeutic potential in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity

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