CXCR2 Is Necessary for the Development and Persistence of Chronic Fungal Asthma in Mice

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.

Section: Figure 10mentioning

confidence: 47%

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

Park

Wiekowski²,

Lira

et al. 2006

“…The progression of lung chemokine production during the development of allergic airway inflammation is well documented (22,55,56), and the requirement of chemokines MDC, TARC, CXCR2, and CCR6 for disease manifestation has been described previously (29,(31)(32)(33). Other chemokine and chemokine receptors such as CCR1 and C10 are involved in inflammation-associated airway remodeling (30,57,58).…”

Section: Discussionmentioning

confidence: 99%

Diverse and Potent Chemokine Production by Lung CD11bhigh Dendritic Cells in Homeostasis and in Allergic Lung Inflammation

Beaty

Rose

Sung

2007

163

156

Lung CD11chigh dendritic cells (DC) are comprised of two major phenotypically distinct populations, the CD11bhigh DC and the integrin αEβ7+ DC (CD103+ DC). To examine whether they are functionally distinguishable, global microarray studies and real-time PCR analysis were performed. Significant differences between the two major CD11chigh DC types in chemokine mRNA expression were found. CD11bhigh DC is a major secretory cell type and highly expressed at least 16 chemokine mRNA in the homeostatic state, whereas CD103+ DC highly expressed only 6. Intracellular chemokine staining of CD11chigh lung cells including macrophages, and ELISA determination of sort-purified CD11chigh cell culture supernatants, further showed that CD11bhigh DC produced the highest levels of 9 of 14 and 5 of 7 chemokines studied, respectively. Upon LPS stimulation in vitro and in vivo, CD11bhigh DC remained the highest producer of 7 of 10 of the most highly produced chemokines. Induction of airway hyperreactivity and lung inflammation increased lung CD11bhigh DC numbers markedly, and they produced comparable or higher amounts of 11 of 12 major chemokines when compared with macrophages. Although not a major producer, CD103+ DC produced the highest amounts of the Th2-stimulating chemokines CCL17/thymus and activation-related chemokine and CCL22/monocyte-derived chemokine in both homeostasis and inflammation. Significantly, CCL22/monocyte-derived chemokine exhibited regulatory effects on CD4+ T cell proliferation. Further functional analysis showed that both DC types induced comparable Th subset development. These studies showed that lung CD11bhigh DC is one of the most important leukocyte types in chemokine production and it is readily distinguishable from CD103+ DC in this secretory function.

“…CXCR2-mediated mucus production may also be relevant in other diseases such as chronic obstructive pulmonary disease and asthma (55), where the overproduction of mucus leads to pathological consequences. Having established that CXCR2 has a pathogenic role in RSV infection, it will be interesting to investigate the contribution of other chemokine receptors to RSV-induced disease.…”

Section: Discussionmentioning

confidence: 99%

CXCR2 Regulates Respiratory Syncytial Virus-Induced Airway Hyperreactivity and Mucus Overproduction

Miller

Strieter

Gruber³

et al. 2003

Severe inflammation and mucus overproduction are partially responsible for respiratory syncytial virus (RSV)-induced disease in infants. Using a murine model, we characterized the virally induced chemokine receptors responsible for mediating the pathophysiological response to RSV infection, we found that CXCR2 mRNA was induced at 4 days after RSV infection. Immunohistochemical staining demonstrated that CXCR2 protein was expressed on alveolar macrophages. Immunoneutralization of CXCR2 resulted in decreased airway hyperreactivity relative to the RSV-infected controls. In addition, there was decreased mucus in the bronchoalveolar lavage fluid, decreased periodic-acid Schiff staining, and significantly less mucus-associated gob-5 mRNA and protein in anti-CXCR2-treated mice. The effects of anti-CXCR2 treatment were not a result of differences in viral clearance or neutrophil influx, as these parameters were comparable in both groups of animals. To confirm our immunoneutralization studies, we performed experiments in CXCR2−/− mice. Results in CXCR2−/− mice recapitulated results from our immunoneutralization studies. However, CXCR2−/− mice also showed a statistically significant decrease in muc5ac, relative to RSV-infected wild-type animals. Thus, CXCR2 may be a relevant target in the pathogenesis of RSV bronchiolitis, since it contributes to mucus production and airway hyperreactivity in our model of RSV infection.