Innate immunity and chronic rhinosinusitis: What we have learned from animal models

Abstract

Objective: Chronic rhinosinusitis (CRS) is a heterogeneous and multifactorial disease characterized by dysregulated inflammation. Abnormalities in innate immune function including sinonasal epithelial cell barrier function, mucociliary clearance, response to pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs), and the contribution of innate immune cells will be highlighted in this review.

Data sources: PubMed literature review.

Review methods: A review of the literature was conducted to determine what we have learned from animal models in relation to innate immunity and chronic rhinosinusitis.

Results: Dysregulation of innate immune mechanisms including sinonasal barrier function, mucociliary clearance, PAMPs, and innate immune cells such as eosinophils, mast cells, and innate lymphoid cells may contribute to CRS pathogenesis. Sinonasal inflammation has been studied using mouse, rat, rabbit, pig, and sheep explant or in vivo models. Study using these models has allowed for analysis of experimental therapeutics and furthered our understanding of the aforementioned aspects of the innate immune mechanism as it relates to sinonasal inflammation. These include augmenting mucociliary clearance through activation of the cystic fibrosis transmembrane conductance regulator (CFTR) and study of drug toxicity on ciliary beat frequency. Knockout models of Toll-like receptors (TLR) have demonstrated the critical role these PRRs play in allergic inflammation as loss of TLR2 and TLR4 leads to decreased lower airway inflammation. Mast cell deficient mice are less susceptible to ovalbumin-induced sinonasal inflammation.

Conclusion: Animal models have shed light as to the potential contribution of dysregulated innate immunity in chronic sinonasal inflammation.

Conflict of interest statement

Conflict of interest statement: N.R.L. has stock in Navigen Pharmaceuticals which is currently of no value. A.P.L. declares no conflicts of interest.

Figures

Figure 1

Interplay between innate immune mechanisms may contribute to CRS pathophysiology. Microbial stimuli such as bacteria, viruses, and parasites and nonmicrobial stimuli such as allergens, particulate matter, and toxins are combated by mucociliary clearance and sinonasal epithelial barrier function to prevent exposure to the underlying tissue. PAMPs and DAMPs acting through PRRs such as extraoral taste receptors may activate an immediate and rapid counter response, whereas additional PRR downstream signaling through TLRs may activate other and likely redundant mechanisms, resulting in inflammatory cytokine release. In the case of CRSsNP, TGF‐β, and IFN‐γ release contribute to Th1 polarization, fibrosis, tissue remodeling, and neutrophil accumulation. In the case of CRSwNP, TSLP, IL‐25, and IL‐33 act on ILC2 and dendritic cells to promote a Th2 T and B cell response. Subsequent IL‐5 release results in eosinophil accumulation and IgE induces protease release from mast cells. M2 macrophages are also recruited in CRSwNP. IL‐13 release further stimulates secretion of mucus, surfactant, and antimicrobial peptides such as human beta defensins, acidic mammalian chitinase, lysozyme, lactoferrin, complement components, and cathelicidins. CRS = chronic rhinosinusitis; CRSsNP = CRS without nasal polyps; CRSwNP = CRS with nasal polyps; DAMP = damage‐associated molecular patterns; IFN‐γ = interferon‐γ; IL‐ = interleukin; ILC = innate lymphoid cells; PAMP = pathogen‐associated molecular patterns; PRR = pattern recognition receptors; TGF‐β = transforming growth factor beta; Th = T‐helper; TLR = toll‐like receptors; TSLP = thymic stromal lymphopoietin.