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Stat6-deficient mice develop airway hyperresponsiveness and peribronchial fibrosis during chronic fungal asthma
Kate Blease1, Jane M Schuh, Claudia Jakubzick
1Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-0602, USA.
Abstract:
Signal transducer and activator of transcription 6 (Stat6) is critical for Th2-mediated responses during allergic airway disease. To investigate the role of Stat6 in fungus-induced airway hyperresponsiveness and remodeling, Stat6-deficient (Stat6-/-) and Stat6-wildtype (Stat6+/+) mice were sensitized to Aspergillus fumigatus and airway disease was subsequently assessed in both groups at days 21, 30, 38, and 44 after an intratracheal challenge with live A. fumigatus conidia. At all times after conidia, histological analysis revealed an absence of goblet cell hyperplasia and markedly diminished peribronchial inflammation in Stat6-/- mice in contrast to Stat6+/+ mice. Airway hyperresponsiveness and peribronchial fibrosis in Stat6-/- mice were significantly reduced at day 21 after conidia compared with Stat6+/+ mice, but both groups exhibited significant, similar increases in these parameters at all subsequent times after conidia. In separate experiments, IL-13-responsive cells in Stat6-/- mice were targeted via the daily intranasal administration of 200 ng of IL-13-PE38QQR (IL13-PE), comprised of human IL-13 and a derivative of Pseudomonas exotoxin, from days 38 to 44 after the conidia challenge. IL13-PE treatment abolished airway hyperresponsiveness, but not peribronchial fibrosis in Stat6-/- mice. Taken together, these data demonstrate that the chronic development of airway hyperresponsiveness during fungal asthma is IL-13-dependent but Stat6-independent.
Insights
Chronic fungal asthma airway hyperresponsiveness is IL-13 dependent but Stat6 independent. Stat6 deficiency reduced early inflammation and hyperresponsiveness to Aspergillus fumigatus.
Area of Science:
- Immunology
- Respiratory Medicine
- Allergy Research
Background:
- Signal transducer and activator of transcription 6 (Stat6) plays a key role in Th2-mediated responses in allergic airway disease.
- Investigating the specific role of Stat6 in fungus-induced airway hyperresponsiveness and remodeling is crucial for understanding fungal asthma pathogenesis.
Purpose of the Study:
- To elucidate the role of Stat6 in the development of airway hyperresponsiveness and remodeling induced by Aspergillus fumigatus.
- To determine whether IL-13 signaling is sufficient to drive chronic airway changes independently of Stat6.
Main Methods:
- Stat6-deficient (Stat6-/-) and wildtype (Stat6+/+) mice were sensitized to Aspergillus fumigatus and challenged intratracheally with conidia.
- Airway hyperresponsiveness, peribronchial inflammation, and fibrosis were assessed at multiple time points post-challenge.
- In Stat6-/- mice, IL-13-PE38QQR (IL13-PE) was administered to target IL-13-responsive cells.
Main Results:
- Stat6-/- mice showed reduced goblet cell hyperplasia and peribronchial inflammation compared to Stat6+/+ mice.
- While early airway hyperresponsiveness and fibrosis were reduced in Stat6-/- mice, these parameters increased similarly to Stat6+/+ mice at later time points.
- IL13-PE treatment in Stat6-/- mice abolished airway hyperresponsiveness but did not affect peribronchial fibrosis.
Conclusions:
- Chronic airway hyperresponsiveness in fungal asthma is dependent on IL-13 but independent of Stat6.
- Stat6 signaling is important for the early stages of inflammation and hyperresponsiveness in this model.
- Targeting IL-13 may be a therapeutic strategy for fungal asthma, even in the absence of Stat6-mediated responses.