New insights into upper airway innate immunity

Abstract

Background: Protecting the upper airway from microbial infection is an important function of the immune system. Proper detection of these pathogens is paramount for sinonasal epithelial cells to be able to prepare a defensive response. Toll-like receptors and, more recently, bitter taste receptors and sweet taste receptors have been implicated as sensors able to detect the presence of these pathogens and certain compounds that they secrete. Activation of these receptors also triggers innate immune responses to prevent or counteract infection, including mucociliary clearance and the production and secretion of antimicrobial compounds (e.g., defensins).

Objective: To provide an overview of the current knowledge of the role of innate immunity in the upper airway, the mechanisms by which it is carried out, and its clinical relevance.

Methods: A literature review of the existing knowledge of the role of innate immunity in the human sinonasal cavity was performed.

Results: Clinical and basic science studies have shown that the physical epithelial cell barrier, mucociliary clearance, and antimicrobial compound secretion play pivotal innate immune roles in defending the sinonasal cavity from infection. Clinical findings have also linked dysfunction of these defense mechanisms with diseases, such as chronic rhinosinusitis and cystic fibrosis. Recent discoveries have elucidated the significance of bitter and sweet taste receptors in modulating immune responses in the upper airway.

Conclusion: Numerous innate immune mechanisms seem to work in a concerted fashion to keep the sinonasal cavity free of infection. Understanding sinonasal innate immune function and dysfunction in health and disease has important implications for patients with respiratory ailments, such as chronic rhinosinusitis and cystic fibrosis.

Figure 1.

Mechanisms involved in sinonasal epithelial innate immunity. Airway surface liquid (ASL) is made up of two layers: A mucus layer (top) and a periciliary fluid layer (PCL) (bottom). The mucus layer is largely composed of sticky mucin proteins produced by goblet cells and submucosal exocrine glands (not depicted) that trap inhaled pathogens. Ciliated epithelial cells similarly are responsible for regulating ASL secretion into both the mucus layer and the PCL as well as regulating ciliary beating. Ciliary beating is facilitated by the PCL, which surrounds the cilia and allows them to beat rapidly, and drives mucociliary clearance, which removes trapped pathogens from the sinonasal cavity. Ciliated epithelial cells also secrete antimicrobial peptides and reactive oxygen and nitrogen species capable of directly killing pathogenic microbes. In cases of prolonged pathogenic exposure, sinonasal epithelial cells secrete cytokines, which activate an inflammatory response and recruit immune cells.

Figure 2.

Bitter taste receptor T2R38 innate immune signaling pathway in sinonasal ciliated epithelial cells. Gram-negative bacteria secrete acyl-homoserine lactone quorum sensing molecules (AHL) as a form of microbial communication. These bitter compounds bind to the bitter taste receptor T2R38, expressed in sinonasal ciliated epithelial cells, which activates a biochemical cascade and leads to a calcium (Ca²⁺) signal that mediates nitric oxide synthase (NOS) dependent nitric oxide (NO) production. NO upregulates ciliary beating, enhances mucociliary clearance of trapped pathogens, and directly kills bacteria after diffusing into the airway surface liquid.

Figure 3.

Taste receptors expressed in solitary chemosensory cells regulate an innate immune response. The presence of pathogens in the upper airway has a two-pronged effect that mediates a calcium (Ca²⁺) response in solitary chemosensory cells. Yet unidentified bitter compounds secreted by microbes bind to and activate bitter taste receptors (T2R). The resulting calcium signal propagates to surrounding epithelial cells, which results in the rapid secretion of antimicrobial peptides (AMP) that directly kill pathogenic microbes. This pathway is attenuated by physiologic glucose levels in the airway surface liquid via sweet taste receptors (T1R2/3), which suppress the calcium response. However, during times of active infection, pathogens consume glucose, which lower levels and facilitates activation of the T2R pathway.