Disease relevance of CXCR3

• Strong CXCR3 expression was also seen in splenic marginal zone lymphoma (14 of 14 cases) and in the monocytoid and plasmacytic cells in extranodal marginal zone lymphoma (15 of 16 cases) [1].
• CXCR3 immunohistochemical or flow cytometric expression was seen in 37 of 39 cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (diffusely positive in 33 cases), whereas mantle cell lymphoma (30 cases), follicular lymphoma (27 cases), and small noncleaved cell lymphoma (8 cases) were negative in all but 2 cases [1].
• Coexpression of CXCR3 and its ligand, Mig, may be an important functional interaction in B-CLL, as well as a useful diagnostic marker for the differential diagnosis of small cell lymphomas [1].
• These results suggest that CXCR3 inhibitors may be promising therapeutic agents for treatment of LN metastasis, including that of melanoma [2].
• Finally, we observed intense expression of CXCL10 and CXCR3 in association with human breast cancer in situ, indicating that these observations may be of pathophysiologic significance [3].

Psychiatry related information on CXCR3

• In the present study we identified a link between CXCL10 overexpression in the brain and human immunodeficiency virus dementia and demonstrated the presence of the chemokine CXCL10 and its receptor, CXCR3, in the neurons in the brains of macaques with simian human immunodeficiency virus encephalitis [4].
• Here we report the presence of the chemokine receptor CXCR3 and its ligand, IP-10, in normal and Alzheimer's disease (AD) brains [5].
• CONCLUSION: Because IP-10 levels correlate closely with histological findings in postoperative BA patients, it would appear to play a specific role in hepatocyte death and hepatic artery changes, thus providing important information about progressive fibrosis in BA patients that facilitates treatment decision making and prediction of prognosis [6].

High impact information on CXCR3

• In addition, PDCs down-regulate CXCR3 and L-selectin, which mediate migration and homing of these cells into the lymph node [7].
• The inducible CXCR3 ligands control plasmacytoid dendritic cell responsiveness to the constitutive chemokine stromal cell-derived factor 1 (SDF-1)/CXCL12 [8].
• An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as functional receptor for platelet factor 4 [9].
• Because pDCs express both the lymph node homing molecule l-selectin and the cutaneous homing molecule cutaneous lymphocyte antigen, the cooperation between inducible CXCR3 ligands and constitutive SDF-1/CXCL12 may regulate recruitment of pDCs either in lymph nodes or at peripheral sites of inflammation [8].
• These multiple activities are apparently mediated by a unique G protein-coupled receptor, termed CXCR3 [9].

Chemical compound and disease context of CXCR3

• Skin biopsies from lichen planus, chronic discoid lupus erythematosus, allergic patch test reactions, psoriasis, and Jessner's lymphocytic infiltration of the skin were investigated for chemokine expression using RNA in situ hybridization, and for the expression of CXCR3 using immunohistochemistry [10].
• Potential role of the chemokine receptors CXCR3, CCR4, and the integrin alphaEbeta7 in the pathogenesis of psoriasis vulgaris [11].
• Periplocoside E inhibits experimental allergic encephalomyelitis by suppressing interleukin 12-dependent CCR5 expression and interferon-gamma-dependent CXCR3 expression in T lymphocytes [12].
• Interphotoreceptor retinoid-binding protein and retinal arrestin (S-antigen) are targets of autoantibodies in human uveitis and are chemotactic for CXC chemokine receptor 5 (CXCR5)- and/or CXCR3-expressing iDC [13].
• In this study, we investigated the therapeutic efficacy of a novel small-molecule compound, TAK779, an antagonist targeting both CCR5 and CXCR3 in intestinal ischemia/reperfusion (I/R) injury [14].

Biological context of CXCR3

• We used three in vivo models to demonstrate a role for CXCR3 in the development of transplant rejection [15].
• Here, we describe a distinct, previously unrecognized receptor named CXCR3-B, derived from an alternative splicing of the CXCR3 gene that mediates the angiostatic activity of CXCR3 ligands and also acts as functional receptor for CXCL4 [9].
• CXCR3 requires tyrosine sulfation for ligand binding and a second extracellular loop arginine residue for ligand-induced chemotaxis [16].
• In this study, we performed an extensive mutational analysis to identify the CXCR3 and heparin binding sites of murine IP-10 [17].
• This correlated with studies using recombinant chemokines, which revealed that I-TAC was the most potent inducer of CXCR3 down-regulation and of transendothelial migration [18].

Anatomical context of CXCR3

• When polarized T cell lines were analyzed, CXCR3 was found to be expressed at high levels on T helper cell (Th)0s and Th1s and at low levels on Th2s [19].
• We also report that the CXCR3 ligand, Mig, is coexpressed on tumor cells in many cases of CLL/SLL (10 of 13 cases examined) with Mig expression less frequently seen in other B-cell lymphoma subtypes [1].
• CXCR3 is a G-protein-coupled seven-transmembrane domain chemokine receptor that plays an important role in effector T-cell and NK cell trafficking [16].
• We report the novel finding that CXCR3 is also expressed on CD34(+) hematopoietic progenitors from human cord blood stimulated with granulocyte-macrophage colony-stimulating factor (GM-CSF) but not on freshly isolated CD34(+) progenitors [20].
• In vitro, HepG2 cells secreted functional chemotactic factors for tumor-derived lymphocytes that could be inhibited using anti-CCR5 or anti-CXCR3 monoclonal antibodies (MoAbs) [21].

Associations of CXCR3 with chemical compounds

• Second, CXCR3(-/)- allograft recipients treated with a brief, subtherapeutic course of cyclosporin A maintained their allografts permanently and without evidence of chronic rejection [15].
• Mutations of charged and uncharged residues in the loop regions of residues 20-24 and 46-47, which caused reduced heparin binding, also resulted in reduced CXCR3 binding and signaling [17].
• The functionality of chemokine receptors CCR5 and CXCR3 on gammadelta T cells was demonstrated by Ca(2+) mobilization and chemotactic response to the respective chemokines [22].
• The N-terminal residue Arg-8, preceding the first cysteine, was critical for CXCR3 signaling [17].
• Here, we investigated the capacity of CXCR3 ligands to modulate allergen-driven IFNgamma production by healthy and allergic individuals characterized by Th1 and Th2 immunity-dominated allergen specific responses, respectively [23].

Physical interactions of CXCR3

• NMR structure of CXCR3 binding chemokine CXCL11 (ITAC) [24].
• Truncated CXCL11 [CXCL11(3-73)] had an eightfold reduced potential to bind and to regulate CXCR3, but was completely inactive in calcium flux and chemotaxis assays [25].
• NBI-74330 was selective for CXCR3 because it showed no significant inhibition of chemotactic responses to other chemokines and did not inhibit radioligand binding to a panel of nonchemokine G-protein coupled receptors [26].
• A CXCR3 variant carrying the CXCR4 binding pocket was constructed by simultaneous lysine-to-alanine and serine-to-glutamate substitutions at positions 300 and 304 of the CXCR3 receptor [27].

Regulatory relationships of CXCR3

• The PBMCs of patients with newly diagnosed but not with longstanding type 1 diabetes showed reduced expression of the Th1-associated chemokine receptors CCR5 (P < 0.001 vs. control subjects) and CXCR3 (P < 0.002 vs. control subjects) [28].
• A functional IFN-gamma-inducible protein-10/CXCL10-specific receptor expressed by epithelial and endothelial cells that is neither CXCR3 nor glycosaminoglycan [29].
• These results suggest that chemokines that attract Th1 cells via CXCR3 can concomitantly block the migration of Th2 cells in response to CCR3 ligands, thus enhancing the polarization of T cell recruitment [30].
• Infiltrating T cells around high endothelial venules in RA synovium and 90 +/- 3% of SF CD3(+)CD4(+) T cells expressed CXCR3, and 85 +/- 2% of SF CD3(+)CD4(+) T cells expressed CCR5 [31].
• After activation, 84% of PBLs expressed CCR5, 90% expressed CXCR3 and 19% expressed CX3CR1 [32].
• These data suggest that IKK2 is also involved in the IFN-gamma-stimulated release of the CXCR3 ligands through a novel mechanism that is independent NF-kappaB [33].

Other interactions of CXCR3

• The chemotactic activity of the Mtb-infected DC supernatants was evaluated by migration assays using activated NK, CD4(+), and CD8(+) cells that expressed both CCR5 and CXCR3 [34].
• While studying responses that are mediated by these two receptors, we found that the agonists for CXCR3 act as antagonists for CCR3 [30].
• Following in vitro activation of purified CD4 T cells, only CCR2 was internalized, whereas expression of CXCR3 was retained in activated CD4 cells [35].
• In addition, radiolabeled human 6Ckine does not bind to either human CXCR3 or mouse CXCR3 [36].
• Eotaxin, therefore, may be a natural CXCR3 antagonist [37].

Analytical, diagnostic and therapeutic context of CXCR3

• We studied the expression of CXCR3 in renal biopsies by immunohistochemistry (n = 45), and real time RT-PCR (n = 78) [38].
• Quantitative real-time PCR confirmed these findings and revealed up-regulated mRNA levels of another chemoattractant that activates CXCR3, monokine induced by IFN-gamma (Mig; CXCL9) [39].
• By immunofluorescence microscopy and flow cytometry, we found that CXCR3 was rapidly internalized when T cells were incubated with IFN-gamma-activated human saphenous vein endothelial cells (HSVEC), but not with resting HSVEC [18].
• Percentages of pulmonary lymphocytes expressing CXCR3 + and CCR5 + (T H 1) and CCR4 + and CCR3 + (T H 2) chemokine receptors were determined in BALF by flow cytometry [40].
• Our data provide a rationale that blocking CXCR3 and CCR5 may offer a unique therapeutic approach to prevent episodes of acute rejection in the early phase after renal transplantation [41].

References