Role of Tim-3 in hepatitis B virus infection: An overview

Liu, Yuan; Gao, Lifen; Liang, Xiaohong; Hong, Chun Pyo

doi:10.3748/wjg.v22.i7.2294

Cited by 36 publications

(42 citation statements)

References 77 publications

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“…Increased evidence demonstrated the dynamic expression and diverse functions of Tim-3 in different disease models, especially in liver diseases including viral hepatitis, acute alcohol hepatitis, and HCC. 17,32,33 Our present study demonstrated that Tim-3 expression in fatty livers of NASH mice was significantly increased and acted as a modulator in the process of NASH (Fig. 1).…”

Section: Discussionsupporting

confidence: 59%

Increased Tim-3 expression alleviates liver injury by regulating macrophage activation in MCD-induced NASH mice

et al. 2018

Cell Mol Immunol

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As an immune checkpoint, Tim-3 plays roles in the regulation of both adaptive and innate immune cells including macrophages and is greatly involved in chronic liver diseases. However, the precise roles of Tim-3 in nonalcoholic steatohepatitis (NASH) remain unstated. In the current study, we analyzed Tim-3 expression on different subpopulations of liver macrophages and further investigated the potential roles of Tim-3 on hepatic macrophages in methionine and choline-deficient diet (MCD)-induced NASH mice. The results of flow cytometry demonstrated the significantly increased expression of Tim-3 on all detected liver macrophage subsets in MCD mice, including F4/80CD11b, F4/80CD68, and F4/80CD169 macrophages. Remarkably, Tim-3 knockout (KO) significantly accelerated MCD-induced liver steatosis, displaying higher serum ALT, larger hepatic vacuolation, more liver lipid deposition, and more severe liver fibrosis. Moreover, compared with wild-type C57BL/6 mice, Tim-3 KO MCD mice demonstrated an enhanced expression of NOX2, NLRP3, and caspase-1 p20 together with increased generation of IL-1β and IL-18 in livers. In vitro studies demonstrated that Tim-3 negatively regulated the production of reactive oxygen species (ROS) and related downstream pro-inflammatory cytokine secretion of IL-1β and IL-18 in macrophages. Exogenous administration of N-Acetyl-L-cysteine (NAC), a small molecular inhibitor of ROS, remarkably suppressed caspase-1 p20 expression and IL-1β and IL-18 production in livers of Tim-3 KO mice, thus significantly reducing the severity of steatohepatitis induced by MCD. In conclusion, Tim-3 is a promising protector in MCD-induced steatohepatitis by controlling ROS and the associated pro-inflammatory cytokine production in macrophages.

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Section: Discussionsupporting

confidence: 59%

Increased Tim-3 expression alleviates liver injury by regulating macrophage activation in MCD-induced NASH mice

et al. 2018

Cell Mol Immunol

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“…[15–22] Importantly, the expressions of PD-1 and TIM-3 in liver tissues of chronic HBV infection and HBV-related HCC are related to the severity of liver inflammation and T cell exhaustion and the prognosis of HCC patients. [17,19,21,23–26] The polymorphisms of PD1 and TIM3 are associated with the development of HBV-associated liver diseases and the prognosis of patients with HBV-related HCC.…”

Section: Introductionmentioning

confidence: 99%

Immune checkpoint proteins PD-1 and TIM-3 are both highly expressed in liver tissues and correlate with their gene polymorphisms in patients with HBV-related hepatocellular carcinoma

Zhu

et al. 2016

Medicine

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Immune checkpoint proteins programmed death-1 (PD-1) and T-cell immunoglobulin domain and mucin domain containing molecule-3 (TIM-3) expression and their gene polymorphisms have separately been shown to be associated with hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). This study simultaneously examined PD-1 and TIM-3 expression in liver tissues and PD1 and TIM3 polymorphisms and analyzed their correlations in 171 patients with HBV-related HCC and 34 patients with HBV-related cirrhosis.PD-1 and TIM-3 expression in liver tissues were examined by immunohistochemistry and the genotypes of PD1 rs10204525 and TIM3 rs10053538 polymorphisms were determined using genomic DNA extracted from peripheral blood as template.Both PD-1 and TIM-3 expressions in liver infiltrating lymphocytes of HCC tumor tissues were significantly higher than those in tumor adjacent tissues or cirrhotic tissues. The elevated PD-1 and TIM-3 expressions were significantly associated with higher tumor grades. The levels between PD-1 and TIM-3 expression in tumor tissues and tumor adjacent tissues had a significant positive intercorrelation. The expressions of PD-1 and TIM-3 in tumor tissues, tumor adjacent tissues, and cirrhotic tissues were significantly associated with PD1 and TIM3 polymorphisms, with genotype AA of PD1 rs10204525 and genotypes GT+TT of TIM3 rs10053538 being associated with significantly increased PD-1 and TIM-3 expression, respectively.These findings support the potential to improve the efficiency of immune checkpoint-targeted therapy and reduce resistance to the therapy by blocking both PD-1 and TIM-3 and suggest the potential to apply the genotype determination of PD1 rs10204525 and TIM3 rs10053538 as biomarkers of immune checkpoint-directed therapies.

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“…Our previous study and other report demonstrated that expression of Tim‐3 was significantly upregulated on monocytes in CHB patients and may play important roles in the pathogenesis of CHB. However, the role of Tim‐3 signalling on function of monocyte in CHB patients has not been well understood …”

Section: Discussionmentioning

confidence: 99%

Tim‐3 regulates inflammatory cytokine expression and Th17 cell response induced by monocytes from patients with chronic hepatitis B

Wang

et al. 2019

Scand J Immunol

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Tim-3 is expressed on monocytes/macrophages and is involved in the regulation of inflammatory responses. The aim of this study was to determine the effect of Tim-3 on inflammatory response triggered by peripheral monocytes from patients with chronic hepatitis B (CHB). Tim-3 expression on peripheral monocytes and frequency of Th17 cells in peripheral blood mononuclear cells (PBMCs) derived from CHB patients were detected. Followed by lipopolysaccharides (LPS) activation of circulating monocytes from CHB patients, expression of inflammatory cytokines including TNF-α，IL-1β and IL-6 were examined in the presence and absence of Galectin-9 which is the ligand for Tim-3. Subsequently, after purified CD4+T cells were cocultured with LPS-activated monocytes from CHB patients in the presence of anti-Tim-3 antibody, percentage of Th17 cells and production of IL-17 were measured. Tim-3 expression was significantly upregulated and closely correlated to the frequency of Th17 cells in patients with CHB. Expression of TNF-α，IL-1β and IL-6 increased significantly in monocytes stimulated with LPS and Galectin-9, compared to LPS stimulation alone. LPS-activated monocytes from CHB patients could drive differentiation of memory CD4+T cells to Th17 cells. However, under the blockade of Tim-3 signalling by anti-Tim-3 antibody, percentage of Th17 cells and production of IL-17 decreased significantly. Our results demonstrate that upregulated expression of Tim-3 on circulating monocytes accelerates inflammatory response by promoting production of inflammatory cytokines and Th17 responses in CHB.How to cite this article: Wang J, Li C, Fu J, Wang X, Feng X, Pan X. Tim-3 regulates inflammatory cytokine expression and Th17 cell response induced by monocytes from patients with chronic hepatitis B. Scand J Immunol. 2019;89:e12755. https://doi.org/ 10.1111/sji.12755 WANG ET AL.

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Role of Tim-3 in hepatitis B virus infection: An overview

Cited by 36 publications

References 77 publications

Increased Tim-3 expression alleviates liver injury by regulating macrophage activation in MCD-induced NASH mice

Increased Tim-3 expression alleviates liver injury by regulating macrophage activation in MCD-induced NASH mice

Immune checkpoint proteins PD-1 and TIM-3 are both highly expressed in liver tissues and correlate with their gene polymorphisms in patients with HBV-related hepatocellular carcinoma

Tim‐3 regulates inflammatory cytokine expression and Th17 cell response induced by monocytes from patients with chronic hepatitis B

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