Respiratory epithelial cells orchestrate pulmonary innate immunity

Abstract

The epithelial surfaces of the lungs are in direct contact with the environment and are subjected to dynamic physical forces as airway tubes and alveoli are stretched and compressed during ventilation. Mucociliary clearance in conducting airways, reduction of surface tension in the alveoli, and maintenance of near sterility have been accommodated by the evolution of a multi-tiered innate host-defense system. The biophysical nature of pulmonary host defenses are integrated with the ability of respiratory epithelial cells to respond to and 'instruct' the professional immune system to protect the lungs from infection and injury.

Figure 1

Structure and function of the innate host defenses in conducting airways. Cartilaginous airways from the terminal bronchioles to the trachea are lined by a pseudostratified epithelium, whose surface is lined by ciliated and secretory cells, that together with submucosal glands, secrete mucins and other host-defense proteins into the periciliary fluids (a,b). Various transcription factors and associated proteins (b, bottom right) are selectively expressed in distinct subsets of epithelial cells lining the airways and submucosal glands. Secreted mucins (blue), such as MUC5AC and MUC5B, produced by goblet cells create a hydrated mucus gel (c,d) that binds particles and pathogens that are moved by the periciliary brush (b) up the airway for clearance from the lungs. Epithelial cells lining the airways and submucosal glands (b,d) create tight epithelial barriers and secrete a diversity of host-defense proteins that recognize microbial pathogens, which enhances the uptake and killing of those pathogens by professional cells of the immune system. The biophysical scaffolds created by the mucus gel, tight cell-cell junctions and communication among respiratory epithelial cells provide multiple barriers to infection. The secretion of fluid and mucus is coordinated with the directional beating of cilia (ultrastructure in electronmicrograph in b) mediated by Cnx43.

Figure 2

Integration of surfactant function and innate host defenses in the alveoli. Gas exchange is mediated by the close apposition of type I and type II epithelial cells to the endothelial cells of pulmonary capillaries, which creates an extensive surface area whereon environmental gases create collapsing forces at the hydrated surfaces of the alveoli (a,b). Hopx is a transcription factor selectively expressed in type I cells, and ABCA3 is a surfactant lipid transporter specific for type II epithelial cells in the alveoli (b). Antibody to smooth muscle actin (α-SMA) stains bronchiolar and vascular smooth muscle. Surface tension is diminished by pulmonary surfactant lipids and proteins secreted by type II epithelial cells (c–e) that remain stable during the dynamic compression and expansion of the lungs during ventilation. The biophysical activities of surfactant are integrated with alveolar host-defense functions that are mediated by the structural components of surfactant that have intrinsic antimicrobial activity. Tubular myelin (a,f), formed by surfactant proteins SP-A and SP-B, and lipid create a highly structured reservoir of surfactant and host-defense proteins that interact with alveolar macrophages and other cells of the immune system to bind to and remove microbial pathogens and ‘instruct’ inflammatory cells to mount appropriate host-defense responses (b). Alveolar epithelial cell and alveolar macrophages directly interact via Cnx43 channels to modify local inflammatory signals and regulate the expression of cytokines and chemokines in response to pathogens. The sizes of surfactant pools are maintained by the synthesis, secretion and reuptake of lipids and proteins by alveolar epithelial cells and by the catabolic activities of alveolar macrophages via processes regulated by GM-CSF that together maintain near sterility of the alveoli (a).

Figure 3

Signaling via PAMPs and DAMPs in respiratory epithelial cells and downstream host-defense responses. PAMPs derived from commensal microbes or respiratory pathogens and DAMPs generated from cell stress and/or death within both the conducting airways and alveoli are recognized via membrane-associated or cytosolic PRRs expressed in respiratory epithelial cells. The binding of ligands to these receptors results in the activation of epithelial cell–intrinsic signaling pathways (via MAPK, IRFs, reactive oxygen species (ROS) and NF-κB) and subsequent production of cytokines, chemokines and antimicrobial proteins that recruit and activate cells of the innate and adaptive immune systems and regulate barrier function. These same recognition pathways in epithelial cells can stimulate autophagy, phagocytosis and the clearance of necrotic cells and pathogens and thus further influence local inflammatory responses. dsRNA, double-stranded RNA.