Modulation of CXCR1 and CXCR3 expression on NK cells via Tim-3 in a murine model of primary biliary cholangitis. (July 2021)

• Record Type: Journal Article
• Authors: Xu, Jiamin; Fu, Haiyan; Yang, Yina; Yu, Haiyan; Ai, Xin; Lei, Yunjie; Bao, Weimin; Tang, Yingmei
• Is Part Of: Molecular immunology. Volume 135(2021)
• Page Start: 342
• Page End: 350
• Publication Date: 2021-07
• Subjects: Tim-3 -- Primary biliary cholangitis -- NK cells -- CXCR1 -- CXCR3; Immunochemistry -- Periodicals; Molecular biology -- Periodicals; Immunochemistry -- Periodicals; Allergy and Immunology -- Periodicals; Molecular Biology -- Periodicals; Immunochimie -- Périodiques; Biologie moléculaire -- Périodiques; Immunochemistry; Molecular biology; Periodicals; Electronic journals; 571.96
• DOI: 10.1016/j.molimm.2021.04.014
• Languages: English
• ISSNs: 0161-5890

Abstract

Graphical abstract: Highlights: An increase of liver-infiltrating NK cells which exhibited high expression of Tim3, CXCR1 and CXCR3 in PBC mice. Dysregulation of Tim-3 and Gal-9 expression is involved in modulating the local immune microenvironment in PBC mice. The potential of Tim-3 pathway to modulate chemokine responses in NK cells during autoimmunity. Abstract: Tim-3, which is expressed on a variety of innate immune cells including NK cells, plays a key role in many autoimmune diseases. However, the immunomodulatory actions of Tim-3 on NK cells in primary biliary cholangitis (PBC) remain uncertain. Using a murine model of PBC we evaluated the expression of Tim-3 and its ligand Gal-9 in peripheral blood, liver, and spleen. Additionally, we studied Tim-3 regulation of chemokine receptors (CXCR1 and CXCR3) in vitro . Flow cytometric analysis indicated large numbers of infiltrating NK cells in the liver which exhibited high expression of Tim-3 and CXCR3. Moreover, we found overexpression of CXCR1 in liver tissue and liver-derived NK cells in PBC mice. We also observed lower levels of soluble Tim-3 in the serum of PBC mice. In vitro experiments with liver-derived NK cells from PBC mice indicated that CXCR3 was up-regulated by treatment with recombinant mouse TIM-3 Fc (rmTim-3 Fc) to activate the Tim-3 pathway. Furthermore, stimulating normal mouse spleen NK cells with poly I:C resulted in elevated expression of CXCR1 and interferon-γ release. Nonetheless, adding rmTim-3 Fc or rmGal-9 significantly down-regulated CXCR1 expression and IFN-γ release in NK cells activated by poly I:C, proposing a means to exploit the Tim-3 pathway to reverse responses in NK cells. In conclusion, our data demonstrate that dysregulation of Tim-3/Gal-9 is involved in modulating the local immune microenvironment in PBC mice. Our findings highlight the potential of Tim-3 pathway to modulate chemokine responses in NK cells during autoimmunity.