Barrier function of airway tract epithelium

Ganesan, Shyamala; Comstock, Adam T; Sajjan, Uma S

Adherens junctions are located just below the tight junctions and mechanically connect adjacent cells and initiate the formation and maturation of cell-cell contacts. The principal proteins in adherens junctions are type I transmembrane glycoprotein, epithelial cadherin (E-cadherin), β-catenin, and α-catenin. An extracellular domain of E-cadherin of adjacent cells forms homotypic, calcium dependent adhesions between epithelial cells. E-cadherin associates with the armadillo protein family member β-catenin and α-catenin, which then forms an interface with the microtubule network and actin cytoskeleton. 114, 115 In addition, E-cadherin also regulates cell proliferation and differentiation by modulating EGFR and β-catenin activities. Under normal conditions, E-cadherin interacts and retains EGFR in adherens junctions of airway epithelium, 116 thus preventing EGFR activation. [117] [118] [119] Dissociation of E-cadherin from the adherens junction complex or reduced expression of E-cadherin, each of which may occur during epithelial to mesenchymal transition, may cause uncoupling and redistribution of EGFR from the adherens junction to the apical cell surface, 120 where it is readily activated by EGF ligands. Excessive activation of EGFR not only promotes cell proliferation, but also development of goblet cell metaplasia/hyperplasia. 57 In fact, enhanced surface expression and phosphorylation of EGF receptors in the airway epithelium has been observed in patients with asthma who show impaired mucosal barrier function. 121 Recently, we demonstrated that EGF receptor phosphorylation is also increased in COPD airway epithelial cells, which retains the phenotype of goblet cell hyperplasia. 122, 123 β-catenin cooperates with E-cadherin to form adherens junctions. 124 However, when dissociated from E-cadherin β-catenin translocates to the nucleus and activates canonical Wnt/βcatenin signaling, thus promoting cell proliferation and suppressing cell-differentiation. 125, 126 Since cigarette smoke causes aberrant activation of canonical Wnt/β-catenin signaling, 127, 128 it is plausible that chronic cigarette smoke exposure decreases barrier function and facilitates invasion of airway epithelium by environmental allergens, pollutants, and pathogens. In asthma bacteria can also cause transient disruption of tight or adherens junctions. [93] [94] [95] Host factors, such as interferons and tumor necrosis factor-α expressed in response to infection may prolong tight junction disruption long after infection is cleared, enabling the passage of inhaled allergens and pollutants. 96, 97 The formation of apico-lateral junctional complexes is closely related to cell polarization. Recent gene arrays indicated the expression of two polarity complexes in airway epithelial cells: the Crumbs (CRB) complex and the partitioning defective (PAR) complex. 90 The CRB complex consists of the integral membrane protein Crumbs3 and the scaffolding proteins, protein associated with Lin seven 1 (PALS1), and PALS1-associated tight junction protein (PATJ). [98] [99] [100] The CRB complex plays a critical role in the formation of tight junctions, cell polarization, and ciliogenesis. 101 Decreased expression of Crumbs3 delays formation of tight junctions and cilia. 101, 102 Depletion of PALS1 leads to the loss of PATJ, disruption of cell polarity, decreased TER, and altered trafficking of E-cadherin. 103, 104 Coronavirus envelope protein E binds to PALS1, and ectoexpression of prote