The intestinal epithelium is an integral component of a communications network

Abstract

The epithelial lining of the intestine forms a barrier that separates the intestinal lumen from the host's internal milieu and is critical for fluid and electrolyte secretion and nutrient absorption. In the early 1990s, my laboratory discovered that intestinal epithelial cells could alter their phenotype and produce proinflammatory chemokines and cytokines when stimulated by pathogenic enteric luminal microbes or proinflammatory agonists produced by cells in the underlying mucosa. It is now well accepted that intestinal epithelial cells can be induced to express and secrete specific arrays of cytokines, chemokines, and antimicrobial defense molecules. The coordinated release of molecules by intestinal epithelial cells is crucial for activating intestinal mucosal inflammatory responses as well as mucosal innate and adaptive immune responses. More recent studies have focused on the intestinal epithelial signaling pathways that culminate in immune activation as well as the role of these pathways in host defense, mucosal injury, mucosal wound healing, and tumorigenesis. The emerging picture indicates that intestinal epithelial cells represent an integral component of a highly regulated communications network that can transmit essential signals to cells in the underlying intestinal mucosa, and that intestinal epithelial cells, in turn, serve as targets of mucosal mediators. These signals are essential for maintaining intestinal mucosal defense and homeostasis.

Figure 1. Epithelial cells represent an integral component of a communications network.

(A) Intestinal epithelial cells can be induced to express chemokines and cytokines in response to encounter with enteric microbial pathogens. These include chemokines that chemoattract neutrophils (CXCL8, CXCL1, CXCL3, and CXCL5; dark blue), macrophages and DCs (CCL2; red), DCs and memory T cells (CCL20; orange), DCs and Th2 cells (CCL22; yellow), Th1 cells (CXCL9, CXCL10, and CXCL11; purple), plasma cells (CCL28; green), α4β7 T cells (CCL25, also known as TECK; light blue), and cytokines (e.g., TNF-α and GM-CSF; magenta). (B) Enteric microbial pathogens in the intestinal lumen can associate with the epithelial cell surface (i), invade epithelial cells and reside within those cells (ii), invade epithelial cells and the underlying mucosa (lamina propria) (iii), or activate surface receptors, such as TLRs (iv). In response, the intestinal epithelium can change its phenotype to produce chemokines and cytokines (v) that act on underlying cells of the innate and adaptive immune system in the lamina propria (vi). Cells in the lamina propria, in turn, produce mediators (vii) that act on cytokine and chemokine receptors on intestinal epithelial cells. Epithelial cells also express TLRs that respond to microbial products (e.g., bacterial flagellin signals through TLR5) and chemokine receptors (CCR6, CXCR4, CCR5, and CX3CR1) and can be induced to produce antimicrobial peptides (AMPs), such as -defensins and cathelicidin (viii).