Neutrophils regulate airway responses in a model of fungal allergic airways disease.
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.
Park
Stacy J
SJ
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, 75390, USA.
Wiekowski
Maria T
MT
Lira
Sergio A
SA
Mehrad
Borna
B
D000818:Animals; D001228:Aspergillosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001232:Aspergillus fumigatus / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006967:Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D008171:Lung Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000276:immunology / Q000502:physiology*; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism; D019076:Transgenes / Q000235:genetics
D016207:Cytokines; D007073:Immunoglobulin E; D020780:Matrix Metalloproteinase 9