Neutrophils Regulate Airway Responses in a Model of Fungal Allergic Airways Disease

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.

Adenosine A2BReceptor Deficiency Promotes Host Defenses against Gram-Negative Bacterial Pneumonia

“…In vivo neutrophil depletion was induced by intraperitoneal administration of 400 mg of monoclonal antibody (mAb) against Ly6G (clone 1A8; Bio X Cell, West Lebanon, NH) or isotype control mAb (clone 2A3; Bio X Cell) as described (20). Methods for tissue harvest (21), bronchoalveolar lavage, and isolation of bone marrow neutrophils (22) and histology (19,21) have been described previously.…”

TNF-α from inflammatory dendritic cells (DCs) regulates lung IL-17A/IL-5 levels and neutrophilia versus eosinophilia during persistent fungal infection

“…During acute infection, neutrophils are crucial for antifungal defense (8,9), and lack of neutrophils is the best appreciated risk factor for invasive aspergillosis (10). However, uncontrolled neutrophil infiltration in Aspergillus-induced allergic disorders positively correlates with tissue damage and loss of lung function (6,11). Because the control of neutrophils is highly desirable in these diseases, there is considerable interest in understanding the mechanisms that promote and perpetuate pulmonary neutrophilia (12).…”

Gene Expression Profiling of Bronchoalveolar Lavage Cells during Aspergillus Colonization of the Lung Allograft

“…For example, gene expression of the Glu-Leu-Arg (ELR) + CXC chemokine neutrophil chemoattractants, CXC chemokine ligand 1 (CXCL1), CXC chemokine ligand 6 (CXCL6), and CXC chemokine ligand 8 (CXCL8), were all increased with Aspergillus colonization, as were CXC chemokine receptor type 1 (CXCR1) and CXC chemokine receptor type 2 (CXCR2), the major CXC chemokine receptors on neutrophils. 33 Importantly, neutrophil mediated response is critical in limiting invasive infections, 34,35 and the preservation of this response may explain why most Aspergillus colonization cases post-lung transplant do not develop invasive disease.…”