Trends in Immunology
ReviewE-cadherin: gatekeeper of airway mucosa and allergic sensitization
Section snippets
Asthma and the airway epithelial phenotype
Asthma is an inflammatory airway disease that affects up to 300 million people worldwide and is characterized by paroxysmal and chronic symptoms, such as wheezing, sputum production, variable airflow limitation, and airway hyperresponsiveness to endogenous or exogenous bronchospasmogenic stimuli.
The airway epithelium forms a continuous, highly regulated physical barrier lining of the airway lumen, which prevents invasion of inhaled environmental agents such as aeroallergens, pollutants and
E-cadherin: the epithelial gatekeeper
Intercellular epithelial junctions form the structural adhesive forces of the mucosal barrier, which separate the underlying tissue from the environment and enable communication between cells, establishment of cell polarity, and transcellular ion transport. These intercellular junctions are comprised of tight junctions (TJs), adherens junctions (AJs) and desmosomes (Figure 1). TJs localize apically and are considered the main regulators of paracellular permeability and movement of ions and
E-cadherin regulates airway epithelial innate immune function
The regulation of the response to environmental stimuli by E-cadherin extends well beyond the cell-autonomous regulation of the epithelial phenotype and barrier function. The airway epithelium is part of the innate immune system, and has a prominent regulatory role in the immune response to environmental triggers 22, 23. Many of the signaling pathways activated by environmental stimuli converge on the transcriptional activation of nuclear factor (NF)-κB in the airway epithelium, and NF-κB
Role of E-cadherin and CD103+ immune cells in tolerance induction
In addition to the cell-autonomous control of proinflammatory epithelial activity, E-cadherin is a ligand for the cognate receptor CD103 (αEβ7 integrin), which is expressed on cells of the innate and adaptive immune system, including T cells and dendritic cells (DCs). CD103 marks mucosal intraepithelial T cell populations in the intestine, urogenital tract and airway mucosa. CD103 is also expressed on a specific population of regulatory CD4+CD25+Foxp3+ T cells (Tregs), which are capable of
Inside-out traffic: E-cadherin in transepithelial migration
Under physiological conditions, leukocytes can migrate across the epithelium into the airway lumen without disrupting the epithelial barrier [44]. Under pathological conditions, however, the transepithelial migration of large numbers of leukocytes inflicts epithelial damage; both through mechanical forces and release of soluble mediators that induce the loss of AJs and TJs [44], which leads to loss of barrier function and even epithelial denudation [44]. For instance, release of elastase by
Effects of inhaled environmental allergens on the regulation of E-cadherin
Proteolytically active allergens can directly and indirectly cause disruption of E-cadherin-mediated contacts, by proteolytic activity and by inducing activation of pattern-recognition receptors (PRRs). Various allergens contain protease activity, including house dust mite (HDM), cockroach, fungi, cat and pollen 47, 48. HDM can induce proteolytic cleavage of the TJ protein occludin and to a lesser extent E-cadherin. This proteolytic activity has been proposed as a major determinant in the
Concluding remarks: a role for E-cadherin in asthma
The phenotype of the airway epithelium that is induced by the interaction of genotype and environment might play a central role in the pathogenesis of allergic asthma. The pathways that govern the immunological and structural phenotype of the asthmatic airway epithelium are functionally and molecularly closely intertwined. E-cadherin is present on the airway epithelium, and data suggest that it controls the outcome of the response to allergens through its interaction with Tregs and DCs, to
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