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Measuring Phagocytosis of Aspergillus fumigatus Conidia by Human Leukocytes using Flow Cytometry
Published on: December 7, 2019
Aspergillus fumigatus induction of IL-33 expression in chronic rhinosinusitis is PAR2-dependent
Caroline J Dietz1,2, Hua Sun1,2, William C Yao1
1Department of Otolaryngology-Head and Neck Surgery, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, U.S.A.
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.
Insights
Aspergillus fumigatus protease induces IL-33 in chronic rhinosinusitis with nasal polyps (CRSwNP) via PAR2. This pathway highlights a potential therapeutic target for CRSwNP treatment.
Area of Science:
- Immunology
- Microbiology
- Otorhinolaryngology
Background:
- Chronic rhinosinusitis with nasal polyps (CRSwNP) involves allergic inflammation driven by IL-13.
- Aspergillus fumigatus (A. fumigatus) upregulates IL-33 in sinonasal epithelial cells (SNECs), activating innate lymphoid cells.
- The precise mechanism of A. fumigatus-induced IL-33 expression in CRSwNP remains unclear.
Purpose of the Study:
- Identify the fungal component(s) responsible for increased IL-33 expression in CRSwNP SNECs.
- Determine the specific receptor mediating A. fumigatus-induced IL-33 upregulation.
- Investigate the role of fungal proteases and PAR2 in CRSwNP pathophysiology.
Main Methods:
- Primary SNECs from CRSwNP patients were stimulated with fungal components.
- Inhibitors of serine protease and protease-activated receptor 2 (PAR2) were used.
- IL-33 and PAR2 expression levels were quantified using qRT-PCR and immunohistochemistry.
Main Results:
- Fungal protease, not cell wall components, elevated IL-33 expression in SNECs.
- PAR2 expression was significantly higher in inflamed mucosa of CRSwNP patients compared to controls.
- The increase in IL-33 was dependent on serine protease activity and PAR2 signaling.
Conclusions:
- A. fumigatus serine protease induces IL-33 expression in CRSwNP SNECs through PAR2.
- This pathway represents a potential therapeutic target for CRSwNP.
- Targeting the A. fumigatus protease-PAR2 interaction may reduce allergic inflammation in CRSwNP.
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