Epithelial adhesion molecules and the regulation of intestinal homeostasis during neutrophil transepithelial migration

Abstract

Epithelial adhesion molecules play essential roles in regulating cellular function and maintaining mucosal tissue homeostasis. Some form epithelial junctional complexes to provide structural support for epithelial monolayers and act as a selectively permeable barrier separating luminal contents from the surrounding tissue. Others serve as docking structures for invading viruses and bacteria, while also regulating the immune response. They can either obstruct or serve as footholds for the immune cells recruited to mucosal surfaces. Currently, it is well appreciated that adhesion molecules collectively serve as environmental cue sensors and trigger signaling events to regulate epithelial function through their association with the cell cytoskeleton and various intracellular adapter proteins. Immune cells, particularly neutrophils (PMN) during transepithelial migration (TEM), can modulate adhesion molecule expression, conformation, and distribution, significantly impacting epithelial function and tissue homeostasis. This review discusses the roles of key intestinal epithelial adhesion molecules in regulating PMN trafficking and outlines the potential consequences on epithelial function.

Keywords: AJs, adherens junctions; CAR, coxsackie and adenovirus receptor; CLMP, CAR-like protein; CTLs, cytotoxic T lymphocytes; CTX, thymocyte Xenopus; DMs, Desmosomes; Dsc-2, desmocollin-2; Dsg-2, desmoglein-2; E-cadherin, epithelial cadherin; EGFR, Epithelial growth factor receptor; EMT, epithelial-mesenchymal transition; EpCAM, epithelial cell adhesion molecule; IBD, inflammatory bowel diseases; ICAM-1, intercellular adhesion molecule-1; IECs, intestinal epithelial cells; JAM, junctional adhesion molecules; LAD, leukocyte adhesion deficiency; LTB-4, lipid leukotriene B4; MIP1 α, macrophage inflammatory protein 1 alpha; MLCK, myosin light chain kinase; MMPs, matrix metalloproteases; NF-κB, nuclear factor kappa B; NO, nitric oxide; PARS, protease-activated receptors; PI3K, phosphatidylinositol 3-kinase; PMN, polymorphonuclear cells; SGD, specific granule deficiency; SIRPa, signal regulatory protein alpha; TEM, transepithelial migration; TGF-β, transforming growth factor beta; TIAM1, metastasis-inducing protein 1; TJs, tight junctions; TSP-1, thrombospondin-1; adhesion molecules; barrier; cell migration; epithelial cells; neutrophils; sLea, sialyl Lewis A.

Figure 1.

Recruitment of circulating PMNs into the intestinal lumen. Upon release of a pro-inflammatory stimulus, circulating PMNs initiate contact with the endothelium resulting in PMN tethering/rolling (1), followed by firm adhesion and crawling (2), and terminating with migration across the endothelial monolayer, primarily at the junctional regions (3). After crossing the endothelium, PMNs navigate through the interstitium (4) until they arrive at the epithelium and engage in basolateral surface interactions (5). PMNs migrating across epithelium navigate between adjacent epithelial cells where they encounter desmosomes, adherens junctions, tight junctions, and other basolaterally expressed epithelial ligands, such as CD47 (6). After crossing the epithelial layer, PMNs emerge at the luminal (apical) surface where they engage apically expressed epithelial ligands, including ICAM-1, CD55, and CD44 (7). Finally, PMNs released into luminal spaces will apoptose and be cleared or, alternatively, accumulate in the crypt lumen to form abscesses, as observed under pathological conditions.

Figure 2.

PMNs migrating across epithelial monolayers in vitro significantly alter TJ protein expression and localization. PMNs (red) migrating across epithelial monolayers grown on permeable supports in a physiologically relevant basolateral to apical direction, locally downregulate/trigger internalization of junctional proteins including occludin (green, left panel) and E-cadherin (green, right panel). Both panels are projections of images acquired in series in Z-direction (apical to basolateral). Left panel depicts PMN during initial contact with the basolateral surface of the epithelial monolayer, prior to TEM (early TEM, indicated by the white arrow), and PMN emerging at the apical epithelial membrane (late TEM, indicated by the white arrow). During early phases of PMN TEM, occludin expression patterns are not yet perturbed, however as PMN migrate across the epithelium loss of occludin can be observed. Similarly, internalization and loss of E-cadherin is observed during late phases of PMN TEM (right panel). Thus, migrating PMNs can significantly impact tissue homeostasis through junctional protein expression/distribution modulation. The bar is 20μm.