Neutrophils regulate airway responses in a model of fungal allergic airways disease
Stacy J Park1, Maria T Wiekowski, Sergio A Lira
1Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, 75390, USA.
Abstract:
Neutrophils infiltrate airway walls in patients with allergic airway diseases and in animal models of these illnesses, but their contribution to the pathogenesis of airway allergy is not established. We hypothesized that, in a mouse model of airway allergy to the ubiquitous environmental mold, Aspergillus fumigatus, airway neutrophils contribute to disease severity. Ab-mediated neutrophil depletion resulted in reduced airway hyperresponsiveness and remodeling, whereas conditional transgenic overexpression of the neutrophil chemotactic molecule, CXCL1, in airway walls resulted in worsened allergic responses. This worsened phenotype was associated with a marked increase in the number of airway neutrophils but not other lung leukocytes, including eosinophils and lymphocyte subsets, and depletion of neutrophils in sensitized mice with transgenic overexpression of CXCL1 resulted in attenuated airway responses. The number of lung neutrophils correlated with lung matrix metalloproteinase 9 (MMP-9) activity both in the context of neutrophil depletion and with augmented neutrophil recruitment to the airways. Although wild-type and MMP-9-deficient neutrophils homed to the inflamed airways to a similar extent, transfer of wild-type, but not MMP-9-deficient, neutrophils to MMP-9-deficient animals resulted in augmented allergic airway responses. Taken together, these data implicate neutrophils in the pathogenesis of fungal allergic airway disease.
Insights
Neutrophils play a key role in fungal allergic airway disease severity. Reducing neutrophils lessened airway hyperresponsiveness and remodeling in a mouse model, highlighting their pathogenic contribution.
Area of Science:
- Immunology
- Pulmonary Medicine
- Allergy Research
Background:
- Neutrophils infiltrate airways in allergic diseases, but their specific role in pathogenesis is unclear.
- Allergic airway diseases, such as those caused by Aspergillus fumigatus, affect many individuals, necessitating a deeper understanding of underlying mechanisms.
Purpose of the Study:
- To investigate the contribution of neutrophils to the severity of allergic airway disease in a mouse model.
- To determine the role of the neutrophil-attracting molecule CXCL1 and matrix metalloproteinase 9 (MMP-9) in fungal-induced airway allergy.
Main Methods:
- Used a mouse model of allergic airway disease induced by Aspergillus fumigatus.
- Employed antibody-mediated neutrophil depletion and transgenic overexpression of CXCL1.
- Assessed airway hyperresponsiveness, airway remodeling, and leukocyte populations (neutrophils, eosinophils, lymphocytes).
- Investigated the role of matrix metalloproteinase 9 (MMP-9) using wild-type and MMP-9-deficient neutrophils and animals.
Main Results:
- Neutrophil depletion reduced airway hyperresponsiveness and remodeling.
- Overexpression of CXCL1 worsened allergic responses, correlating with increased airway neutrophils.
- Neutrophil numbers correlated with lung matrix metalloproteinase 9 (MMP-9) activity.
- MMP-9-competent neutrophils, but not MMP-9-deficient neutrophils, augmented allergic responses when transferred to MMP-9-deficient recipients.
Conclusions:
- Neutrophils are implicated in the pathogenesis of fungal allergic airway disease.
- Neutrophil recruitment and activity, particularly MMP-9, contribute to disease severity.
- Targeting neutrophils may offer therapeutic strategies for fungal allergic airway diseases.
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