Disease relevance of Ccl25

• Antibody Blockade of CCL25/CCR9 Ameliorates Early but not Late Chronic Murine Ileitis [1].
• Yet different from patients with primary sclerosing cholangitis, the expression of CCL25 remained restricted to the small intestine, even in mice with inflammation of the biliary tree [1].
• Furthermore, although clinical trials to evaluate the efficacy of targeting the CCL25/CCR9 axis for the treatment of Crohn's disease are being conducted, preclinical data in animal models of IBD are lacking [1].
• Methods: In the current studies, we investigated the expression of CCL25 and CCR9 as a function of disease progression in a spontaneous murine model of chronic ileitis (SAMP1/YitFc) using flow cytometry, real-time reverse-transcription polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemistry [1].

High impact information on Ccl25

• These findings provide profound in vivo evidence that CCL25/CCR9 guides PCs into the small intestine [2].
• These recently activated CCR9(+) CD8alphabeta(+) lymphocytes selectively localized to the small-intestinal mucosa, and in vivo neutralization of the CCR9 ligand, CCL25, reduced the ability of these cells to populate the small-intestinal epithelium [3].
• CCL25 mediates the localization of recently activated CD8alphabeta(+) lymphocytes to the small-intestinal mucosa [3].
• Together these results demonstrate an important role for chemokines in the localization of T lymphocytes to the small-intestinal mucosa and suggest that targeting CCL25 and/or CCR9 may provide a means to selectively modulate small-intestinal immune responses [3].
• Background & Aims: CCL25 mediates the homeostatic recruitment of CCR9-expressing lymphocytes to the small intestine, but the function of this chemokine/receptor pair during chronic small intestinal inflammation has yet to be determined [1].

Biological context of Ccl25

• TECK specifically induces a calcium flux and chemotaxis of GPR-9-6-transfected cells [4].
• The TECK receptor gene was isolated and shown to be localized on the mouse chromosome 9F1-F4 [5].
• In contrast, most immature and medullary thymocytes migrate to thymus-expressed chemokine, an ability that is lost only with up-regulation of the peripheral homing receptor L-selectin during the latest stages of thymocyte maturation associated with export to the periphery [6].
• Mature CD8+ thymocytes have a similar alpha(E) integrin(+) CCL25 responsive phenotype, as do adult CD8+ RTE identified by intrathymic FITC injection [7].
• CCR9 mediates chemotaxis of thymocytes in response to CCL25/thymus-expressed chemokine, and its mRNA is selectively expressed in thymus and small intestine, the two known sites of T lymphopoiesis [8].

Anatomical context of Ccl25

• Consistently, in mice orally immunized with cholera toxin (CT), anti-CCL25 suppressed homing of CT-specific IgA ASCs into small intestine, whereas anti-CCL28 suppressed homing of CT-specific IgA ASCs into both small intestine and colon [9].
• In conclusion, the interplay of TECK and its receptor CCR9 is likely to have a significant role in the recruitment of developing thymocytes to discrete compartments of the thymus [5].
• In contrast, our results indicate that thymic epithelial cells constitute the predominant source of TECK [5].
• Thymic dendritic cells have been initially thought to be a prevalent source of TECK [5].
• The aim of this study was to examine whether thymus-expressed chemokine (TECK)/CCL25 and its ligand CCR9 are involved in T-lymphocyte interaction with microvessels of murine intestinal mucosa [10].

Associations of Ccl25 with chemical compounds

• Neonatal CD8+ splenocytes uniformly express alpha(E) integrin and exhibit a high responsiveness to CC chemokine ligand (CCL25) (as compared with adult CD8+ splenocytes) [7].
• The levels of IL-7, SDF-1alpha, TECK, and SLC mRNA inversely correlated with the kinetics of regeneration [11].

Other interactions of Ccl25

• Reciprocally, CT-specific ASCs and IgA titers in the blood were increased in mice treated with anti-CCL25 or anti-CCL28 [9].
• Murine CCR9, a chemokine receptor for thymus-expressed chemokine that is up-regulated following pre-TCR signaling [4].
• Increased expression of TECK/CCL25 by TNF-alpha was observed in the lamina propria of small intestine [10].
• The in vivo significance of this finding is demonstrated by studies in the nude mouse where the thymic anlage lacks TECK and SDF-1 expression and prothymocytes home to the parathyroid anlage rather than to the thymic anlage [12].
• However, fetal thymus colonization was markedly diminished by neutralizing antibodies specific for CCL21 and CCL25, but not affected by anti-CXCL12 antibody [13].

References