Modulation of CXCR1 and CXCR3 expression on NK cells via Tim-3 in a murine model of primary biliary cholangitis

Xu, Jiamin; Fu, Huiling; Yang, Yina; Yu, Haiyan; Ai, Xin; Yunjie, LEI; Bao, Weimin; Tang, Ying‐Mei

doi:10.1016/j.molimm.2021.04.014

Cited by 7 publications

(4 citation statements)

References 30 publications

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“…In a murine model of PBC, a large number of NK cells infiltrate into the liver and express CXCR3 at high levels, which is associated with the chemotaxis, localization, activation, and killing functions of NK cells. 52 In addition, CXCR3 induced a Th2 bias in iNKT cells of WT mice, which can be associated with ANIT-induced CLI. In triptolide-induced CLI, the percentage of CXCR3 + IL-4 + iNKT cells and CXCR3 + IL-17 + iNKT cells was remarkably elevated, and a Th1 bias of CD4 + T cells was induced by CXCR3.…”

Section: Discussionmentioning

confidence: 99%

“…In this study, our results showed that the expression of CXCR3 on the surface of IFN-γ + NK cells and IL-4 + NK cells significantly increased in ANIT-administered WT mice, and the proportion of these two cells was not significantly changed in CXCR3-deficient mice. In a murine model of PBC, a large number of NK cells infiltrate into the liver and express CXCR3 at high levels, which is associated with the chemotaxis, localization, activation, and killing functions of NK cells . In addition, CXCR3 induced a Th2 bias in iNKT cells of WT mice, which can be associated with ANIT-induced CLI.…”

Section: Discussionmentioning

confidence: 99%

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Detrimental Role of CXCR3 in α-Naphthylisothiocyanate- and Triptolide-Induced Cholestatic Liver Injury

Mei,

Li,

et al. 2023

Chem. Res. Toxicol.

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The chemokine receptor CXCR3 is functionally pleiotropic, not only recruiting immune cells to the inflamed liver but also mediating the pathological process of cholestatic liver injury (CLI). However, the mechanism of its involvement in the CLI remains unclear. Both alphanaphthylisothiocyanate (ANIT) and triptolide are hepatotoxicants that induce CLI by bile acid (BA) dysregulation, inflammation, and endoplasmic reticulum (ER)/oxidative stress. Through molecular docking, CXCR3 is a potential target of ANIT and triptolide. Therefore, this study aimed to investigate the role of CXCR3 in ANIT-and triptolide-induced CLI and to explore the underlying mechanisms. Wild-type mice and CXCR3-deficient mice were administered with ANIT or triptolide to compare CLI, BA profile, hepatic recruitment of IFN-γ/IL-4/IL-17 + CD4 + T cells, IFN-γ/IL-4/IL-17 + iNKT cells and IFN-γ/IL-4 + NK cells, and the expression of ER/oxidative stress pathway. The results showed that CXCR3 deficiency ameliorated ANIT-and triptolide-induced CLI. CXCR3 deficiency alleviated ANIT-induced dysregulated BA metabolism, which decreased the recruitment of IFN-γ + NK cells and IL-4 + NK cells to the liver and inhibited ER stress. After triptolide administration, CXCR3 deficiency ameliorated dysregulation of BA metabolism, which reduced the migration of IL-4 + iNKT cells and IL-17 + iNKT cells and reduced oxidative stress through inhibition of Egr1 expression and AKT phosphorylation. Our findings suggest a detrimental role of CXCR3 in ANIT-and triptolide-induced CLI, providing a promising therapeutic target and introducing novel mechanisms for understanding cholestatic liver diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Detrimental Role of CXCR3 in α-Naphthylisothiocyanate- and Triptolide-Induced Cholestatic Liver Injury

Mei,

Li,

et al. 2023

Chem. Res. Toxicol.

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“…CXCR3 is a chemokine receptor that is primarily expressed on CD4 + and CD8 + T cells, and to some extent by other cells, among them, macrophages [ 166 ], NK cells [ 167 , 168 , 169 ], and epithelial cells [ 170 ]. Within the CD4 + subset, CXCR3 is most abundant on effector T cells, but notably, it is also expressed by FOXp3+ regulatory T cells (T regs ) In humans, three isoforms were identified: CXCR3A that is reciprocal to the mouse CXCR3 and binds CXCL9, CXCL10, and CXCL11, CXCR3-B that binds CXCL9, CXCL10, CXCL11 as well as an additional ligand CXCL4, and CXCR3-alt that only binds CXCL11 [ 171 ].…”

Section: Key Chemokine-chemokine Receptor Interactions That Limit Tumor Growthmentioning

confidence: 99%

Chemokines in the Landscape of Cancer Immunotherapy: How They and Their Receptors Can Be Used to Turn Cold Tumors into Hot Ones?

Karin

2021

Cancers

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Over the last decade, monoclonal antibodies to immune checkpoint inhibitors (ICI), also known as immune checkpoint blockers (ICB), have been the most successful approach for cancer therapy. Starting with mAb to cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors in metastatic melanoma and continuing with blockers of the interactions between program cell death 1 (PD-1) and its ligand program cell death ligand 1 (PDL-1) or program cell death ligand 2 (PDL-2), that have been approved for about 20 different indications. Yet for many cancers, ICI shows limited success. Several lines of evidence imply that the limited success in cancer immunotherapy is associated with attempts to treat patients with “cold tumors” that either lack effector T cells, or in which these cells are markedly suppressed by regulatory T cells (Tregs). Chemokines are a well-defined group of proteins that were so named due to their chemotactic properties. The current review focuses on key chemokines that not only attract leukocytes but also shape their biological properties. CXCR3 is a chemokine receptor with 3 ligands. We suggest using Ig-based fusion proteins of two of them: CXL9 and CXCL10, to enhance anti-tumor immunity and perhaps transform cold tumors into hot tumors. Potential differences between CXCL9 and CXCL10 regarding ICI are discussed. We also discuss the possibility of targeting the function or deleting a key subset of Tregs that are CCR8+ by monoclonal antibodies to CCR8. These cells are preferentially abundant in several tumors and are likely to be the key drivers in suppressing anti-cancer immune reactivity.

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“…Several factors impact the phenotype and function of NK cells in liver disease, such as aging [25], calorie restriction [26], hepatitis viral infection [27], primary biliary cholangitis [28], HCC microenvironment [29], etc. In this review, we focus on the roles of NK cells in liver fibrosis, especially for the molecules that impact the interaction of NK cells with HSCs.…”

Section: Introductionmentioning

confidence: 99%

The Important Roles of Natural Killer Cells in Liver Fibrosis

Yang,

Vanderwert,

Kimchi

et al. 2023

Biomedicines

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Liver fibrosis accompanies the development of various chronic liver diseases and promotes their progression. It is characterized by the abnormal accumulation of extracellular matrix proteins (ECM) and impaired ECM degradation. Activated hepatic stellate cells (HSCs) are the major cellular source of ECM-producing myofibroblasts. If liver fibrosis is uncontrolled, it may lead to cirrhosis and even liver cancer, primarily hepatocellular carcinoma (HCC). Natural killer (NK) cells are a key component of innate immunity and have miscellaneous roles in liver health and disease. Accumulating evidence shows that NK cells play dual roles in the development and progression of liver fibrosis, including profibrotic and anti-fibrotic functions. Regulating NK cells can suppress the activation of HSCs and improve their cytotoxicity against activated HSCs or myofibroblasts to reverse liver fibrosis. Cells such as regulatory T cells (Tregs) and molecules such as prostaglandin E receptor 3 (EP3) can regulate the cytotoxic function of NK cells. In addition, treatments such as alcohol dehydrogenase 3 (ADH3) inhibitors, microRNAs, natural killer group 2, member D (NKG2D) activators, and natural products can enhance NK cell function to inhibit liver fibrosis. In this review, we summarized the cellular and molecular factors that affect the interaction of NK cells with HSCs, as well as the treatments that regulate NK cell function against liver fibrosis. Despite a lot of information about NK cells and their interaction with HSCs, our current knowledge is still insufficient to explain the complex crosstalk between these cells and hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, B cells, and T cells, as well as thrombocytes, regarding the development and progression of liver fibrosis.

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Modulation of CXCR1 and CXCR3 expression on NK cells via Tim-3 in a murine model of primary biliary cholangitis

Cited by 7 publications

References 30 publications

Detrimental Role of CXCR3 in α-Naphthylisothiocyanate- and Triptolide-Induced Cholestatic Liver Injury

Detrimental Role of CXCR3 in α-Naphthylisothiocyanate- and Triptolide-Induced Cholestatic Liver Injury

Chemokines in the Landscape of Cancer Immunotherapy: How They and Their Receptors Can Be Used to Turn Cold Tumors into Hot Ones?

The Important Roles of Natural Killer Cells in Liver Fibrosis

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