A critical role for IRF5 in regulating allergic airway inflammation.

Interferon regulatory factor 5 (IRF5) is a key transcription factor involved in the control of the expression of proinflammatory cytokine and responses to infection, but its role in regulating pulmonary immune responses to allergen is unknown. We used genetic ablation, adenoviral vector-driven overexpression, and adoptive transfer approaches to interrogate the role of IRF5 in pulmonary immunity and during challenge with the aeroallergen, house dust mite. Global IRF5 deficiency resulted in impaired lung function and extracellular matrix (ECM) deposition. IRF5 was also essential for effective responses to inhaled allergen, controlling airway hyperresponsiveness, mucus secretion, and eosinophilic inflammation. Adoptive transfer of IRF5-deficient alveolar macrophages into the wild-type pulmonary milieu was sufficient to drive airway hyperreactivity, at baseline or following antigen challenge. These data identify IRF5-expressing macrophages as a key component of the immune defense of the airways. Manipulation of IRF5 activity in the lung could therefore be a viable strategy for the redirection of pulmonary immune responses and, thus, the treatment of lung disorders.

Alveolar macrophages are sentinels of murine pulmonary homeostasis following inhaled antigen challenge.

BACKGROUND: Alveolar macrophages are sentinels of the pulmonary mucosa and central to maintaining immunological homeostasis. However, their role in governing the response to allergen is not fully understood. Inappropriate responses to the inhaled environment manifest as asthma. METHODS: We utilized a mechanistic IL-13-driven model and a house dust mite allergen mucosal sensitization model of allergic airway disease to investigate the role of alveolar macrophages in regulating pulmonary inflammation. RESULTS: IL-13-dependent eosinophilic and Th2 inflammation was enhanced in mice depleted of alveolar macrophages using clodronate liposomes. Similarly, depletion of alveolar macrophages during house dust mite sensitization or established disease resulted in augmented Th2 immunity and increased allergen-specific IgG1 and IgE. Clodronate treatment also delayed the resolution of tissue inflammation following cessation of allergen challenge. Strikingly, tissue interstitial macrophages were elevated in alveolar macrophage-deficient mice identifying a new homeostatic relationship between different macrophage subtypes. A novel role for the macrophage-derived immunoregulatory cytokine IL-27 was identified in modulating Th2 inflammation following mucosal allergen exposure. CONCLUSIONS: In summary, alveolar macrophages are critical regulators of Th2 immunity and their dysregulation promotes an inflammatory environment with exacerbation of allergen-induced airway pathology. Manipulating IL-27 may provide a novel therapeutic strategy for the treatment of asthma.

Endothelin-1 directs airway remodeling and hyper-reactivity in a murine asthma model.

BACKGROUND: The current paradigm describing asthma pathogenesis recognizes the central role of abnormal epithelial function in the generation and maintenance of the disease. However, the mechanisms responsible for the initiation of airway remodeling, which contributes to decreased lung function, remain elusive. Therefore, we aimed to determine the role of altered pulmonary gene expression in disease inception and identify proremodeling mediators. METHODS: Using an adenoviral vector, we generated mice overexpressing smad2, a TGF-ß and activin A signaling molecule, in the lung. Animals were exposed to intranasal ovalbumin (OVA) without systemic sensitization. RESULTS: Control mice exposed to inhaled OVA showed no evidence of pulmonary inflammation, indices of remodeling, or airway hyper-reactivity. In contrast, local smad2 overexpression provoked airway hyper-reactivity in OVA-treated mice, concomitant with increased airway smooth muscle mass and peribronchial collagen deposition. Pulmonary eosinophilic inflammation was not evident, and there was no change in serum IgE or IgG1 levels. The profound remodeling changes were not mediated by classical pro-inflammatory Th2 cytokines. However, uric acid and interleukin-1ß levels in the lung were increased. Epithelial-derived endothelin-1 and fibroblast growth factor were also augmented in smad2-expressing mice. Blocking endothelin-1 prevented these phenotypic changes. CONCLUSIONS: Innate epithelial-derived mediators are sufficient to drive airway hyper-reactivity and remodeling in response to environmental insults in the absence of overt Th2-type inflammation in a model of noneosinophilic, noninflammed types of asthma. Targeting potential asthma therapies to epithelial cell function and modulation of locally released mediators may represent an effective avenue for therapeutic design.

Inhaled house dust mite induces pulmonary T helper 2 cytokine production.

BACKGROUND: Inhaled house dust mite (HDM) results in T-helper (TH) 2 type pathology in unsensitized mice, in conjunction with airway hyperreactivity and airway remodelling. However, the pulmonary cytokine and chemokine profile has not been reported. METHODS: We have performed a time course analysis of the characteristic molecular mediators and cellular influx in the bronchoalveolar lavage (BAL) and lung in order to define the pulmonary inflammatory response to inhaled HDM extract. Mice were exposed five times a week to soluble HDM extract for 3 weeks. Lung function was measured in groups of mice at intervals following the final HDM challenge. Recruitment of inflammatory cells and inflammatory mediator production was then assessed in BAL and lungs of individual mice. RESULTS: We found that Th2 cytokines were significantly increased in BAL and lung after HDM challenge from as early as 2 h post-final challenge. The levels of cytokines and chemokines correlated with the influx of eosinophils and Th2 cells to the different compartments of the lung. However, the production of key cytokines such as IL-4, IL-5 and IL-13 preceded the increase in airways resistance. CONCLUSION: Inhaled HDM challenge induces a classical Th2 inflammatory mediator profile in the BAL and lung. These data are important for studies determining the efficacy of novel treatment strategies for allergic airways disease.

Respiratory syncytial virus infection provokes airway remodelling in allergen-exposed mice in absence of prior allergen sensitization.

BACKGROUND: The mechanisms underlying exacerbation of asthma induced by respiratory syncytial virus (RSV) infection have been extensively studied in human and animal models. However, most of these studies focused on acute inflammation and little is known of its long-term consequences on remodelling of the airway tissue. OBJECTIVE: The aim of the study was to use a murine model of prolonged allergen-induced airway inflammation to investigate the effect of RSV infection on allergic airway inflammation and tissue remodelling. METHODS: We subjected mice to RSV infection before or during the chronic phase of airway challenges with OVA and compared parameters of airway inflammation and remodelling at the end-point of the prolonged allergen-induced airway inflammation protocol. RESULTS: RSV infection did not affect the severity of airway inflammation in any of the groups studied. However, RSV infection provoked airway remodelling in non-sensitized, allergen-challenged mice that did not otherwise develop any of the features of allergic airways disease. Increased collagen synthesis in the lung and thickening of the bronchial basal membrane was observed in non-sensitized allergen-challenged mice only after prior RSV infection. In addition, fibroblast growth factor (FGF)-2 but not TGF-beta(1) was increased in this group following RSV infection. CONCLUSION: Our data show for the first time that RSV infection can prime the lung of mice that are not previously systemically sensitized, to develop airway remodelling in response to allergen upon sole exposure via the airways. Moreover, our results implicate RSV-induced FGF-2 in the remodelling process in vivo.

Half-life of human parainfluenza virus type 3 (hPIV3) maternal antibody and cumulative proportion of hPIV3 infection in young infants.

During a phase 2 trial of parainfluenza virus type 3 (PIV3) vaccine, sequential serum samples were obtained from infants at 2, 6, 7, 12-15, and 13-16 months of age. Paired serum samples obtained at 2 and 6 months of age were used to estimate the biologic half-life of human PIV3 (hPIV3) maternal antibody in young infants. On the basis of the assumption that hPIV3 maternal antibody decays exponentially and constantly, the biologic half-life was estimated without adjusting for body weight increases. Cumulative proportions of hPIV3 infection in young infants were further estimated after adjusting for maternal antibody decline. A hemagglutination inhibition assay was used to quantify hPIV3 antibody. The mean (95% confidence interval) biologic half-life was estimated to be 51 (42-60) days, on the basis of which cumulative proportions of hPIV3 infection were estimated to be 11% at 6 months of age, 47% at 12-15 months of age, and 50% at 13-16 months of age.