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. 2014 Jan;4(1):15-21.
doi: 10.1002/alr.21237.

Damage-associated Molecular Patterns Stimulate interleukin-33 Expression in Nasal Polyp Epithelial Cells

Free PMC article

Damage-associated Molecular Patterns Stimulate interleukin-33 Expression in Nasal Polyp Epithelial Cells

Gina Paris et al. Int Forum Allergy Rhinol. .
Free PMC article

Abstract

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a disorder characterized by eosinophilic inflammation and local T-helper 2 (Th2) cytokine production. Innate lymphoid cells that elaborate Th2 cytokines have recently been characterized within nasal polyps. These cells can be activated by the epithelial cell-derived cytokine interleukin-33 (IL-33). The objective of this study is to determine whether 2 molecules associated with tissue damage (high mobility group box-1 [HMGB-1] and adenosine triphosphate [ATP]) elicit expression of IL-33 in sinonasal epithelial cells (SNECs) derived from recalcitrant CRSwNP patients.

Methods: Ethmoid tissue was obtained from 8 recalcitrant CRSwNP and 9 control subjects during endoscopic sinus surgery (ESS). Tissue was prepared for immunohistochemistry and for SNEC air-liquid interface culture. After exposure to either HMGB1 or ATP in vitro, SNECs were processed for messenger RNA (mRNA) extraction and immunocytochemistry. IL-33 levels were determined by real-time polymerase chain reaction (PCR) and by immunochemical staining with anti-IL-33 antibody.

Results: Intranuclear IL-33 is normally expressed in basal epithelial cells, but is present in more apical cells and outside the nucleus in CRSwNP. Exposure of SNECs to HMGB-1 or ATP resulted in a statistically significant increase in IL-33 mRNA expression in SNECs derived from recalcitrant CRSwNP patients. This increase was reflected at the protein level by immunochemical staining of IL-33.

Conclusion: Tissue damage is a nonspecific trigger of epithelial IL-33 production in treatment-recalcitrant polyps, which may be responsible for perpetuating eosinophilic inflammation in CRSwNP. This common pathway may help explain why multiple environmental and infectious agents have been implicated in CRSwNP exacerbation.

Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Figures

Figure 1
Figure 1
Localization of IL-33 protein in ethmoid mucosa in control and CRSwNP subjects. In control ethmoid tissue, IL-33 is expressed primarily by epithelial cells located in a basal location in the epithelium, where it is retained in the nucleus (upper panels, A). In recalcitrant CRSwNP, IL-33 is also expressed largely in the nucleus of basal epithelial cells, but also extends to cells in apical portions of the epithelium and labeling occurs outside the nucleus in many cases, both in the cytoplasm and extracellularly (lower panels, B). Scale bar=25 microns.
Figure 2
Figure 2
The damage-associated molecules, HMGB-1 and ATP induce expression of IL-33 mRNA in sinonasal epithelial cells derived from recalcitrant CRSwNP subjects. Data is expressed as fold increase over unstimulated condition within individual subjects. * p= 0.046; **p=0.033
Figure 3
Figure 3
Stimulation of sinonasal epithelial cell expression of IL-33 with HMGB-1 and ATP. Sinonasal epithelial cells grown at the air-liquid interface were exposed to the damage-associated molecules, HMGB-1 (100 ng/ml) for 24 hours, or ATP (100 μM) for 8 hours. A marked increase in nuclear expression of IL-33 protein was observed in recalcitrant CRSwNP subjects, although the mean increase in nuclear immunofluoresence did not achieve statistical significance for the group as a whole. (A/B: pre- and post-HMGB-1 exposure; C/D: pre- and post-ATP exposure). E: Graphical representation of increase in mean IL-33 immunostaining following exposure to HMGB-1 and ATP, across all subjects (p=ns).

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