Mechanisms and pathogenesis of chronic rhinosinusitis

Abstract

Chronic rhinosinusitis (CRS) is a heterogeneous disease characterized by local inflammation of the upper airways and is historically divided into 2 main phenotypes: CRS with nasal polyps and CRS without nasal polyps. Inflammation in CRS is mainly characterized by 3 endotypes based on elevation of canonical lymphocyte cytokines: type (T) 1 (T1) by T_H1 cytokine IFN-γ, T2 by T_H2 cutokines IL-4, IL-5, and IL-13, and T3 by T_H17 cytokines including IL-17. Inflammation in both CRS without nasal polyps and CRS with nasal polyps is highly heterogeneous, and the frequency of various endotypes varies geographically around the world. This finding complicates establishment of a unified understanding of the mechanisms of pathogenesis in CRS. Sinonasal epithelium acts as a passive barrier, and epithelial barrier dysfunction is a common feature in CRS induced by endotype-specific cytokines directly and indirectly. The sinonasal epithelium also participates in both innate immunity via recognition by innate pattern-recognition receptors and promotes and regulates adaptive immunity via release of chemokines and innate cytokines including thymic stromal lymphopoietin. The purpose of this review was to discuss the contribution of the epithelium to CRS pathogenesis and to update the field regarding endotypic heterogeneity and various mechanisms for understanding pathogenesis in CRS.

Keywords: Chronic rhinosinusitis; endotype; eosinophils; epithelial dysfunction; nasal polyps; neutrophils.

Figure 1.. Epithelial Contributions to CRS

Extrinsic pathogens and irritants interact with multiple epithelial receptors to induce both innate and adaptive immune responses. Protease exposure induces tight junction (TJ) dysfunction and secretion of endogenous protease inhibitors (EPIs) which neutralize extrinsic proteases and stimulate type 2 inflammation. Similarly, pathogen-associated molecular patterns (PAMPs) interact with Toll-like receptors (TLRs) leading to apical anti-microbial peptide (AMP) secretion as well as epithelial derived cytokine secretion. P-glycoprotein (P-gp) functions to clear the cytoplasm of environmental toxins while reinforcing epithelial cytokine release. Epithelial derived exosomes support these innate immune responses by shuttling AMPs directly to mucus borne pathogens while promoting the inter-epithelial transfer of P-gp. Bacterial derived quorum sensing molecules, such as acyl-homoserine lactone (AHL) compounds, also interact with bitter taste receptors such as T2R38 to induce bacteriocidal nitric oxide (NO) release, enhanced mucociliary clearance (MCC), and cytokine/chemokine secretion.

Figure 2.. Potential mechanisms in T2 CRSwNP

Pathogens and environmental factors activate nasal epithelial cells inducing an innate cytokine TSLP. Some countries also found elevation of IL-25 and IL-33. TSLP and PAMPs stimulate DCs to induce naive CD4⁺ T cell differentiation into Th2 cells. These epithelial derived innate cytokines also activate ILC2s, pathogenic Th2 cells and mast cells to produce T2 cytokine. Th2 cells also activate ILC2s to induce T2 cytokines via a RANK-L dependent pathway. IL-4 and IL-13 activate epithelial cells, endothelial cells, macrophages and B cells to induce barrier dysfunction, mucus response, eosinophil recruitment, and IgE-mediated reaction. Epithelial dysfunction is also controlled by activation of eosinophils, neutrophils and complement. Antigen/IgE/IgER complexes on mast cells and basophils induce degranulation and release prestored molecules including histamine and enzymes that induce vascular leak and tissue damage. Plasma leak triggers fibrin deposition in the NPs via crosslinking by FXIIIA released from M2 macrophages and reduction of tPA in epithelial cells. Accumulation of IgG and autoantibodies induce the activation of complements and neutrophils.

Figure 3.. Potential mechanisms in non-T2 CRSwNP

T1 mediated inflammation is mainly triggered by the accumulation and activation of Th1 cells, CD8⁺ T cells and NK cells and IFN-γ is a key cytokine that controls further recruitment of T1 immune cells, epithelial barrier dysfunction, fibrin deposition and development of M1 macrophages. M1 macrophages produce IL-1β and ROS to induce inflammation. T3 mediated inflammation is triggered by the accumulation and activation of Th17 cells. IL-17 induces recruitment of Th17 cells and neutrophils. Activated neutrophils release OSM, NETs, IL-1β, LTB4 enzymes and ROS to induce epithelial barrier dysfunction, inflammation and tissue damage. IgG antibodies are also elevated in non-T2 CRSwNP and may play a role on the activation of neutrophils and complement pathways.