Mice with a Selective Deletion of the CC Chemokine Receptors 5 or 2 Are Protected from Dextran Sodium Sulfate-Mediated Colitis: Lack of CC Chemokine Receptor 5 Expression Results in a NK1.1+ Lymphocyte-Associated Th2-Type Immune Response in the Intestine

Abstract

The chemokine receptors CCR2 and CCR5 and their respective ligands regulate leukocyte chemotaxis and activation. To determine the role of these chemokine receptors in the regulation of the intestinal immune response, we induced colitis in CCR2- and CCR5-deficient mice by continuous oral administration of dextran sodium sulfate (DSS). Both CCR2- and CCR5-deficient mice were susceptible to DSS-induced intestinal inflammation. The lack of CCR2 or CCR5 did not reduce the DSS-induced migration of macrophages into the colonic lamina propria. However, both CCR5-deficient mice and, to a lesser degree, CCR2-deficient mice were protected from DSS-induced intestinal adhesions and mucosal ulcerations. CCR5-deficient mice were characterized by a greater relative infiltration of CD4+ and NK1.1+ lymphocyte in the colonic lamina propria when compared to wild-type and CCR2-deficient mice. In CCR5-deficient mice, mucosal mRNA expression of IL-4, IL-5, and IL-10 was increased, whereas that of IFN-γ was decreased, corresponding to a Th2 pattern of T cell activation. In CCR2-deficient mice, the infiltration of Th2-type T cells in the lamina propria was absent, but increased levels of IL-10 and decreased levels of IFN-γ may have down regulated mucosal inflammation. Our data indicate that CCR5 may be critical for the promotion of intestinal Th1-type immune responses in mice.

CCR6 has a non‐redundant role in the development of inflammatory bowel disease

“…No significant differences were found between WT and CCR6-deficient mice in macrophage infiltrate in the inflamed mucosa, a feature of DSS-mediated colitis. A recent study reported that CCR2-or CCR5-deficient mice are protected from DSS-mediated colitis, despite the fact that these g -chemokine receptor-defective animals and the corresponding WT controls showed similar macrophage infiltrates in intestinal mucosa [36]. In our experiments, estimated CD4 mRNA levels in colon at day 0 and during the acute colitis phase indicated that there were more CD4 + and CD8 + T cells in CCR6-deficient than in WT mouse colons.…”

“…The origin of this increase in T cell transcript levels may be, at least in part, a consequence of altered lymphocyte homeostasis, which provokes a basal increment of those cells in the intestinal mucosa of CCR6-deficient mice [30,31]. Andres et al observed a similar increase in CD4 + /CD8 + T cells when analyzing colitis development in CCR5-deficient mice [36].…”

Chemokines: attractive mediators of the immune response

“…Notably, the induction of a Th1 response by macrophage derived dendritic cells can occur through the interaction between CCR5 and its ligand, independent of IL-12, indicating that chemokines alone can affect T cell differentiation [29]. Indeed, in mice lacking CCR5 there is a skewed Th2 cytokine profile, providing further confirmation that CCR5 is involved in determining T helper cell fate [30]. Viewed together, these data suggest that CCL5-CCR5 interactions are important not only in the initial recruitment of T cells to an inflammatory lesion, but also as determinants for the differentiation of Th1 T cells.…”

Investigation of substituent effect of 1-(3,3-diphenylpropyl)-piperidinyl phenylacetamides on CCR5 binding affinity using QSAR and virtual screening techniques

“…Individuals, who are homozygous for 32-bp deletion in the gene encoding CCR5, whilst otherwise healthy, are strongly protected against infection [2]. Many studies indicate different roles for CCR5 and its ligands in disorders such as rheumatoid arthritis [3], multiple sclerosis [4], transplant rejection [5] and inflammatory bowel disease [6]. These observations suggest that molecules that modulate the CCR5 receptor would have potential benefit in a wide range of diseases.…”