A novel role for constitutively expressed epithelial-derived chemokines as antibacterial peptides in the intestinal mucosa

Abstract

Intestinal-derived chemokines have a central role in orchestrating immune cell influx into the normal and inflamed intestine. Here, we identify the chemokine CCL6 as one of the most abundant chemokines constitutively expressed by both murine small intestinal and colonic epithelial cells. CCL6 protein localized to crypt epithelial cells, was detected in the gut lumen and reached high concentrations at the mucosal surface. Its expression was further enhanced in the small intestine following in vivo administration of LPS or after stimulation of the small intestinal epithelial cell line, mIC(c12), with IFNgamma, IL-4 or TNFalpha. Recombinant- and intestinal-derived CCL6 bound to a subset of the intestinal microflora and displayed antibacterial activity. Finally, the human homologs to CCL6, CCL14 and CCL15 were also constitutively expressed at high levels in human intestinal epithelium, were further enhanced in inflammatory bowel disease and displayed similar antibacterial activity. These findings identify a novel role for constitutively expressed, epithelial-derived chemokines as antimicrobial peptides in the intestinal mucosa.

Sensing of Interleukin-1 Cytokines during Streptococcus pneumoniae Colonization Contributes to Macrophage Recruitment and Bacterial Clearance

“…It acts as a macrophage chemoattractant (42) and is highly expressed in, peripheral eosinophils and elicited macrophages (42,43), as well as lung tissue (44,45) and epithelial cells of the intestinal mucosa (46). The mRNA present in RLT lysis lavage samples from the upper respiratory tract is predominantly derived from epithelial cells of the mucosal barrier, suggesting that these cells are a likely source of CCL6 during pneumococcal colonization.…”

“…The mRNA present in RLT lysis lavage samples from the upper respiratory tract is predominantly derived from epithelial cells of the mucosal barrier, suggesting that these cells are a likely source of CCL6 during pneumococcal colonization. In addition to its chemokine functions, CCL6 may have intrinsic antibacterial properties (46), and overexpression of CCL6 in transgenic mice confers protection against bacterial sepsis (47). Multiple studies have observed that in contrast to CCL2, which is expressed early during inflammation, CCL6 induction occurs later and is sustained for several days to over a week (43,48).…”

Function of the intestinal epithelium and its dysregulation in inflammatory bowel disease

“…176 An array of inducible/inflammatory chemokines such as CXCL 8 177 and CCL20 178 are upregulated in IBD, with early attempts to regulate chemokine levels in IBD patients in vivo showing promising results. 179 In addition to this, constitutive/homeostatic chemokines such as CXCL12 and CCL14 have also been shown to be dysregulated in IBD, 180,181 with others such as CCL25 and CCL28 involved in the trafficking of specific T-cell subsets in the small and large intestine respectively.…”

Role of Antimicrobial Peptides in Inflammatory Bowel Disease

“…Moreover, at least 17 members of the chemokine family have been shown to exert direct antibacterial activity. Epithelial-derived chemokines with constitutive expression include CLL14, CCL15 and CCL20/macrophage-inflammatory protein-3α [7]. Finally, bactericidal/permeability-increasing protein (BPI) is another anti-infective molecule present in the intestinal mucosa.…”