Aspergillus fumigatus induction of IL‐33 expression in chronic rhinosinusitis is PAR2‐dependent

Abstract

Objective In the pathophysiology of chronic rhinosinusitis with nasal polyps (CRSwNP), Aspergillus fumigatus (A. fumigatus) can upregulate IL‐33 from human sinonasal epithelial cells (SNECs), which then activates innate lymphoid cells causing release of IL‐13, an important driver of allergic inflammation. However, the mechanism by which A. fumigatus mediates the induction of IL‐33 expression remains to be elucidated. The objectives of this study were to determine the specific fungal component(s) and the receptor responsible for mediating the A. fumigatus induced increase in IL‐33 expression in SNECs from patients with CRSwNP. Methods SNECs from CRSwNP patients were cultured and stimulated with various fungal components in the absence or presence of 4‐(2‐Aminoethyl)benzenesulfonyl fluoride hydrochloride, an irreversible serine protease inhibitor, or GB83, a reversible protease activated receptor 2 (PAR2) inhibitor. IL‐33 expression was evaluated using quantitative real‐time polymerase chain reaction (qRT‐PCR). PAR2 expression was examined in inflamed mucosa from nonatopic control and CRSwNP patients. Results Elevation of IL‐33 expression in primary SNECs was found in response to fungal protease but not fungal cell wall components. PAR2 expression was elevated in inflamed mucosa from CRSwNP patients in comparison to controls. The A. fumigatus fungal protease‐mediated elevation in IL‐33 expression by human SNECs was serine protease‐ and PAR2‐dependent. Conclusion These data suggest that serine protease activity of A. fumigatus is capable of inducing IL‐33 expression in CRSwNP SNECs via PAR2, a potential therapeutic target in the treatment of CRSwNP. Level of Evidence NA Laryngoscope, 129:2230–2235, 2019

International consensus statement on allergy and rhinology: rhinosinusitis 2021

“…Sinonasal epithelial cells increase IL‐33 expression and production when challenged with fungi 626,627 . This increase in IL‐33 is in part associated with a fungal serine protease activated receptor 2 (PAR2) 628 . In AFRS, PAR2 expression is increased on SNECs 628,629 .…”

“…This increase in IL‐33 is in part associated with a fungal serine protease activated receptor 2 (PAR2) 628 . In AFRS, PAR2 expression is increased on SNECs 628,629 . In addition, fungi can also drive an increased intracellular uptake of calcium via P2X 7 receptor activation that also leads to increase in IL‐33 secretion 627 .…”

A murine model of eosinophilic chronic rhinosinusitis using the topical application of a vitamin D3 analog

“…7 Aspergillus fumigatus is another causative antigen, which induces IL-33 release from sinonasal epithelial cells and enhances Th2-type inflammation. 45 Recently, the imbalance between the coagulation cascade and the fibrinolysis cascade in the nasal mucosa has been reported to predispose to the development of nasal polyps. 46,47 Yet, the TSLP-basophil axis remains to be considered one of the important factors involved in the pathogenesis of ECRS.…”

“…Enterotoxins produced by S aureus not only induce SE‐specific IgE but also serve as a superantigen, enhancing the release of Th2 cytokines from T cells 7 . Aspergillus fumigatus is another causative antigen, which induces IL‐33 release from sinonasal epithelial cells and enhances Th2‐type inflammation 45 . Recently, the imbalance between the coagulation cascade and the fibrinolysis cascade in the nasal mucosa has been reported to predispose to the development of nasal polyps 46,47 .…”

Alternaria alternata Accelerates Loss of Alveolar Macrophages and Promotes Lethal Influenza A Infection

“…In prior studies, intranasal inoculation of mice with A. alternata-derived serine protease (AASP) or the Alp1 protease from A. fumigatus induced allergic airway inflammation and bronchial hyperreactivity [11,60]. Fungal proteases typically promote allergic and inflammatory responses via activation of the receptor, proteinase activated receptor 2 (PAR2; [12,13,61,62]), although protease and PAR2-independent allergic and inflammatory responses to A. alternata have also been reported [15,63,64].…”