Chemokines and chemokine receptors in mucosal homeostasis at the intestinal epithelial barrier in inflammatory bowel disease

Abstract

Chemokines, a large family of small chemoattractive cytokines, and their receptors play an integral role in the regulation of the immune response and homeostasis. The ability of chemokines to attract specific populations of immune cells sets them apart from other chemoattractants. Chemokines produced within the gastrointestinal mucosa are critical players in directing the balance between physiological and pathophysiological inflammation in health, inflammatory bowel disease (IBD), and the progression to colon cancer. In addition to the well-characterized role of chemokines in directed trafficking of immune cells to the gut mucosa, the expression of chemokine receptors on the cells of the epithelium makes them active participants in the chemokine signaling network. Recent findings demonstrate an important role for chemokines and chemokine receptors in epithelial barrier repair and maintenance as well as an intricate involvement in limiting metastasis of colonic carcinoma. Increased recognition of the association between barrier defects and inflammation and the subsequent progression to cancer in IBD thus implicates chemokines as key regulators of mucosal homeostasis and disease pathogenesis.

Figure 1. Expanded role for epithelial-derived chemokines in mucosal inflammation, wound healing, and carcinogenesis

A. Chemokines likely regulate immune cell trafficking in the inflammatory bowel diseases. Increased expression and production of chemokines by epithelial cells in the damaged or intact mucosal barrier direct the elevated trafficking of leukocytes and lymphocytes of the innate and adaptive immune response to the gastrointestinal mucosa. B. Potential roles for chemokines in repair of the epithelial barrier. The homeostatic chemokine CXCL12 is constitutively expressed in the cells of the human intestinal epithelium. In culture model systems CXCL12 activates the canonical restitutive epithelial migration signaling pathway and aids in increased closure of wounded epithelial monolayers. C. Chemokines differentially participate in the progression from dysplastic epithelium to frank tumor and metastasis. Epigenetic silencing of CXCL12 in the colonic carcinoma cells confers metastasis-proficient phenotype to those cells, allowing them to respond to endocrine chemokine gradients (green circles).