Cellular Barriers after Extravasation: Leukocyte Interactions with Polarized Epithelia in the Inflamed Tissue

Abstract

During the inflammatory response, immune cells egress from the circulation and follow a chemotactic and haptotactic gradient within the tissue, interacting with matrix components in the stroma and with parenchymal cells, which guide them towards the sites of inflammation. Polarized epithelial cells compartmentalize tissue cavities and are often exposed to inflammatory challenges such as toxics or infections in non-lymphoid tissues. Apicobasal polarity is critical to the specialized functions of these epithelia. Indeed, a common feature of epithelial dysfunction is the loss of polarity. Here we review evidence showing that apicobasal polarity regulates the inflammatory response: various polarized epithelia asymmetrically secrete chemotactic mediators and polarize adhesion receptors that dictate the route of leukocyte migration within the parenchyma. We also discuss recent findings showing that the loss of apicobasal polarity increases leukocyte adhesion to epithelial cells and the consequences that this could have for the inflammatory response towards damaged, infected or transformed epithelial cells.

Figure 1

Endothelial and epithelial barriers determine the different stages of leukocyte migration in its journey towards the inflammatory focus in complex tissues. The parenchymal three-dimensional organization contributes to establish an haptotactic and chemotactic gradient (1) Leukocyte adhesion and transendothelial migration or diapedesis. (2) Exiting the vessel. Once they reach the subendothelial space, leukocytes traverse the basement membrane and interact with pericytes, which promote the complete extravasation of immune cells via adhesion receptors. (3) Interstitial migration. Leukocytes switch from a two-dimensional to a less adhesive three-dimensional migration to circumvent topological constraints in the stromal barrier. Fibroblasts help leukocyte navigation by maintaining protein scaffolds and secreting mediators such as cytokines and growth factors, which act as chemotactic cues. (4) Interaction with polarized epithelial barriers. Following haptotactic and chemotactic gradients, leukocytes encounter polarized epithelial cells and often undergo transepithelial migration. The polarized distribution of the adhesive and chemotactic machineries mediates leukocyte guidance through the parenchymal epithelia for immunosurveillance or the clearance of pathogens and dysfunctional cells.

Figure 2

Redistribution of surface receptors and soluble chemoattractants upon loss of apicobasal polarity in epithelial cells. (a) In polarized hepatocytes, ICAM-1 is able to reach the basolateral membrane but is rapidly redirected to the apical membrane domains. Upon hepatic cell depolarization or in response to persistent stimulation with the inflammatory cytokine TNFα, ICAM-1 and ezrin-radixin-moesin (ERM) proteins, which connect the receptor to the underlying actin cytoskeleton, are oriented towards the stromal milieu and become accessible to immune cells and small hepatic vessels [7]. Other apically polarized receptors involved in leukocyte adhesion, which also interact with the submembranal actin cytoskeleton, such as CD44 isoforms, should be more exposed to parenchymal immune cells upon loss of apicobasal polarity. (b) Columnar epithelial cells, such as intestinal cells, express on their apical membrane key chemokines and lipid mediators, adhesion receptors and other membrane proteins involved in the mobilization of immune cells to the luminal side of the epithelial barrier during inflammation. The proinflammatory cytokine IFNγ is central to increase the expression of some of these receptors, namely ICAM-1 [8]. TNFα may also contribute, for example, by stimulating IL-8 secretion from the basolateral or the apical membrane domains. Following epithelial pathologies or cell death, epithelial cells acquire a “mesenchymal phenotype” and therefore, it is plausible to speculate about the loss of polarized distribution of immune cues also in these epithelial cells. However, the relationship between apicobasal polarity and leukocyte adhesion remains to be investigated in columnar epithelial cells.