IL-33–Responsive Innate Lymphoid Cells Are an Important Source of IL-13 in Chronic Rhinosinusitis with Nasal Polyps

Abstract

Rationale: Chronic rhinosinusitis (CRS) without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP) are associated with Th1 and Th2 cytokine polarization, respectively; however, the pathophysiology of CRS remains unclear. The importance of innate lymphoid cells in Th2-mediated inflammatory disease has not been clearly defined. Objectives: The objective of this study was to investigate the role of the epithelial cell-derived cytokine IL-33 and IL-33-responsive innate lymphoid cells in the pathophysiology of CRS. Methods: Relative gene expression was evaluated using quantitative real-time polymerase chain reaction. Innate lymphoid cells in inflamed ethmoid sinus mucosa from patients with CRSsNP and CRSwNP were characterized using flow cytometry. Cytokine production from lymphoid cells isolated from inflamed mucosa of patients with CRS was examined using ELISA and intracellular cytokine staining. Chronic rhinosinusitis (CRS) is a chronic inflammatory process of the nasal and paranasal sinus mucosa affecting more than 30 million people annually, resulting in significant direct healthcare costs (1). CRS without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP) are associated with Th1 and Th2 cytokine polarization, respectively (2, 3), although the cellular and molecular mechanisms driving the Th2-mediated inflammation in CRSwNP are not clearly understood (4, 5). Due largely to a lack of understanding of the pathophysiology of CRS, current treatment options, including high-dose glucocorticosteroids and surgeries, remain noncurative, generic, and largely unchanged over the past decade.IL-33, a member of the IL-1 family of cytokines, is expressed by epithelial cells, endothelial cells, fibroblasts, smooth muscle cells, macrophages, and dendritic cells (6-8). The IL-33 receptor, a heterodimeric complex composed of ST2 and IL-1 receptor accessory protein (IL1RAP), is expressed on numerous immune cells, including Th2 cells, mast cells, basophils, eosinophils, and macrophages (7-9). IL-33 is a chemoattractant for Th2 cells (10) and promotes Th2 polarization of naive CD4 1 T cells, enhancing production of IL-5 and IL-13 independent of IL-4 (11). IL-33 can also induce proinflammatory cytokine and chemokine production by mast cells and enhance degranulation (12), stimulate basophils and eosinophils (13), and enhance IL-13-driven polarization of alternatively activated macrophages (14). More recently, an important role for IL-33 in regulating the development and function of type 2 innate lymphoid cells (ILC) was described (15, 16). The epithelial cell-derived cytokine IL-33 is known to play a key role in the development and regulation of a Th2 immune response, mediated in part by an IL-33-responsive innate lymphoid cell population. However, there is little direct evidence of an important role for these cells in Th2-mediated inflammatory disease in humans. What This Study Adds to the FieldHere we show that the percentage of innate lymphoid cells is significantly elevated in diseased mucosa in chronic rhinosinusitis w...

Group 2 Innate Lymphoid Cells in Health and Disease

“…This study also showed that the ILC2s from CRS patients responded to IL-33-mediated stimulation by producing IL-13 (Shaw et al 2013), further suggesting that ILC2s may contribute to the pathogenesis of allergic upper airway disease in humans. Consistent with previous findings (Mjosberg et al 2012), TSLP has recently been shown to be highly expressed in the nasal polyps of CRS patients (Nagarkar et al 2013).…”

“…Multiple reports indicate that IL-33 is a potent activator of IL-13-producing ILC2s in allergic airway inflammation (Bartemes et al 2012;Beamer et al 2012;Mjosberg et al 2012;Salmond et al 2012;Hung et al 2013;Shaw et al 2013), but other epithelial cell-derived cytokines, bioactive lipids, and inflammatory factors also contribute to the development of pathogenic ILC2 responses in the lung. A recent study has shown that TSLP can contribute to ILC2 activation that promotes corticosteroid resistance in the context of IL-33-mediated airway inflammation (Kabata et al 2013).…”

“…Cite this article as Cold Spring Harb Perspect Biol 2015;7:a016337 tients with CRS and nasal polyps in comparison to control CRS patients without nasal polyps (Shaw et al 2013). This study also showed that the ILC2s from CRS patients responded to IL-33-mediated stimulation by producing IL-13 (Shaw et al 2013), further suggesting that ILC2s may contribute to the pathogenesis of allergic upper airway disease in humans.…”

Innate Lymphoid Cells: Immunoregulatory Cells of Mucosal Inflammation

“…ILC22 cells secreting IL-22 in lungs exert an antiinflammatory effect during experimental allergic asthma and inhibit acute hypersensitivity reaction (AHR) and pulmonary inflammation. Besides in asthma, group 2 ILCs also play a significant role in the pathogenesis of chronic rhinosinusitis (CRS) by releasing IL-13 in response to IL-33 released through nasal epithelial cells (18). CRS is a chronic inflammatory condition of the nasal and paranasal sinus mucosa affecting more than 30 million people annually (18).…”

Update in Asthma 2013

“…Past studies established that ILC2 cells were increased in subjects with asthma and nasal polyposis, compared with subjects without allergic inflammation (38). Shaw and colleagues showed that subjects with chronic rhinosinusitis and nasal polyposis had a higher percentage of ILC2 cells compared with subjects with chronic rhinosinusitis alone, and these cells had the capacity to produce IL-13 in response to IL-33 (39). Thus, ILC2 cells from human nasal polyps have the functional capacity to drive allergy and asthma.…”