CCR2 expressing CD4+ T lymphocytes are preferentially recruited to the ileum in Crohn's disease

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Abstract
Background and aims: Chemokine receptors are key determinants of leucocyte trafficking. While the chemokine receptor CCR9 and its chemokine ligand CCL25 (TECK) mediate lymphocyte homing to the healthy small intestine, the chemokine receptors important for recruitment during intestinal inflammation are undefined. Animal studies have suggested potential roles for CCR2 and CCR5 in inflammatory bowel disease (IBD). The aim of this study was to understand the role of CCR2 in human IBD. Methods: Resections of ileum or colon were obtained from patients undergoing surgery for small bowel Crohn’s disease (SBCD; n = 10), Crohn’s colitis (n = 5), ulcerative colitis (n = 6), and non-IBD related conditions (control ileum n = 11; control colon n = 11). Expression of CCR2 by lamina propria lymphocytes (LPLs) was determined by both flow cytometry and immunohistochemistry. As a functional correlate, chemotaxis assays using the CCR2 ligand, CCL2 (MCP-1), were performed. Expression of CCR2 by peripheral blood lymphocytes was determined by flow cytometry. Results: There were greater than 30-fold more CCR2+ LPLs in SBCD than in control ileum (29.3% (19.9–55.1) v 0.9% (0.4–11.5); p = 0.0007). Specifically, CCR2+CD4+ LPLs were increased (p = 0.002) whereas CCR2+CD8+ LPLs were not. Increased expression included both memory (CD45RO+; p = 0.005) and naïve (CD45RO−; p = 0.01) CCR2+ populations. The increase in CCR2+ LPLs in SBCD was confirmed by both immunohistochemistry (p = 0.0002) and enhanced chemotactic responses to CCL2. CCR2 expression was not increased in the peripheral blood of patients with SBCD, suggesting ongoing recruitment of the CCR2+ population to the ileum. In contrast with SBCD, there was no significant increase in CCR2+ LPLs in Crohn’s colitis or ulcerative colitis samples. Conclusions: The chemokine receptor CCR2 appears to be an important contributor to accumulation of CD4+ T lymphocytes in the ileum in small bowel Crohn’s disease. Blockade of CCR2 may provide a novel therapeutic alternative.