Differential expression of CXCR3 targeting chemokines CXCL10, CXCL9, and CXCL11 in different types of skin inflammation

Abstract

Recruitment of activated T-cells to the skin is a common feature in a wide variety of inflammatory skin diseases. As CXCR3 activating chemokines CXCL10 (IP-10), CXCL9 (Mig), and CXCL11 (IP-9/I-TAC) specifically attract activated T-cells, this study addressed the question of whether differences in the expression of these chemokines correlate with the site and cellular composition of the skin infiltrates in different types of inflammatory skin disease. 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. The results showed differential expression of CXCL10, CXCL9, and CXCL11, which correlated with differences in the localization and cellular composition of the infiltrates. Whereas CXCL10 and CXCL11 were mainly expressed by basal keratinoctyes, CXCL9 mRNA expression was located predominantly in the dermal infiltrates. Correlation with immunohistochemical data suggested that macrophages and activated keratinocytes were the main producers of these chemokines. CXCR3 was expressed by a majority of both CD4+ and CD8+ infiltrating T-cells, suggesting a functional interaction between locally produced chemokines and CXCR3-expressing T-cells. In conclusion, these findings indicate that these CXCR3 activating chemokines play a significant role in the recruitment and maintenance of T-cell infiltrates in the inflammatory skin diseases studied.

Immune Surveillance and Effector Functions of CCR10+ Skin Homing T Cells

“…We have analyzed a subset of CKRs that are important in memory T cell biology, and addressed which of these CKRs are coexpressed on CCR10 ϩ memory CD4 T cells. The ligands for CCR4 (16 -18), CCR6 (19,20), and CXCR3 (18,21) are found in inflamed skin, and ligands for CCR7 are found in both lymphoid and peripheral tissues (1). Coexpression of different CKRs investigates the potential for cooperative or redundant mechanisms to facilitate T cell entry into peripheral tissues during immune surveillance or during T cell-mediated disease episodes.…”

Antagonist of interferon‐inducible protein 10/CXCL10 ameliorates the progression of autoimmune sialadenitis in MRL/lpr mice

“…Expression of IP-10 and its receptor CXCR3 has been shown to be associated with the development of several Th1-type human inflammatory diseases, including psoriasis, multiple sclerosis, atherosclerosis, rheumatoid arthritis, and myasthenia gravis (41)(42)(43)(44)(45)(46). In addition, elevated IP-10 gene expression has been found in association with rejection of human cardiac allografts and mouse cardiac, small bowel, and pancreatic islet allografts (47,48).…”

Molecular characterization of the chemokine receptor CXCR3: evidence for the involvement of distinct extracellular domains in a multi‐step model of ligand binding and receptor activation

“…During the past few years, several studies have demonstrated a pathogenetic role of CXCR3 and its ligands in human inflammatory diseases [12][13][14][15][16][17][18]. Blockade of CXCR3 interactions with its ligands in vivo therefore represents a possible therapeutic goal for the treatment of these disorders.…”

“…CXCR3 and its ligands play an important role in the induction and perpetuation of several human inflammatory disorders including autoimmune diseases, arteriosclerosis, transplant rejection and viral infections [12][13][14][15]. Recent studies have shown that the CXCR3 ligands exhibit unique temporal and spatial expression patterns, suggesting that they have nonredundant functions in vivo [16][17][18]. Moreover, the CXCR3 ligands share low sequence homology (around 40% amino acid identity) and exhibit differences in their potencies and efficacies at CXCR3, with CXCL11 being the dominant ligand [11,19].…”