Multistrain Genetic Comparisons Reveal CCR5 as a Receptor Involved in Airway Hyperresponsiveness

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Asthma is etiologically and clinically heterogeneous, making the genomic basis of asthma difficult to identify. We exploited the straindependence of a murine model of allergic airway disease to identify different genomic responses in the lung. BALB/cJ and C57BL/6J mice were sensitized with the immunodominant allergen from the Dermatophagoides pteronyssinus species of house dust mite (Der p 1), without exogenous adjuvant, and the mice then underwent a single challenge with Der p 1. Allergic inflammation, serum antibody titers, mucous metaplasia, and airway hyperresponsiveness were evaluated 72 hours after airway challenge. Whole-lung gene expression analyses were conducted to identify genomic responses to allergen challenge. Der p 1-challenged BALB/cJ mice produced all the key features of allergic airway disease. In comparison, C57BL/6J mice produced exaggerated Th2-biased responses and inflammation, but exhibited an unexpected decrease in airway hyperresponsiveness compared with control mice. Lung gene expression analysis revealed genes that were shared by both strains and a set of down-regulated genes unique to C57BL/6J mice, including several G-protein-coupled receptors involved in airway smooth muscle contraction, most notably the M2 muscarinic receptor, which we show is expressed in airway smooth muscle and was decreased at the protein level after challenge with Der p 1. Murine strain-dependent genomic responses in the lung offer insights into the different biological pathways that develop after allergen challenge. This study of two different murine strains demonstrates that inflammation and airway hyperresponsiveness can be decoupled, and suggests that the downmodulation of expression of G-protein-coupled receptors involved in regulating airway smooth muscle contraction may contribute to this dissociation.

Section: Gene Expression Analysis Reveals Shared and Distinct Patternmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Strain-Dependent Genomic Factors Affect Allergen-Induced Airway Hyperresponsiveness in Mice

Kelada

Wilson

Tavarez

et al. 2011

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“…The gene for one of the antioxidant proteins, peroxiredoxin, was one of the most strongly up-regulated genes in Pneumocystis-infected BALB/c mice. Although this might act as a protective agent in the presence of oxidants, peroxiredoxins also are implicated in the modification of immune cells function (45) as well as the onset of AHR in mice (46). Another interesting gene on this list is CD38.…”

Section: Discussionmentioning

confidence: 99%

Pneumocystis Elicits a STAT6-Dependent, Strain-Specific Innate Immune Response and Airway Hyperresponsiveness

Swain

Meissner²,

Siemsen³

et al. 2012

It is widely held that exposure to pathogens such as fungi can be an agent of comorbidity, such as exacerbation of asthma or chronic obstructive pulmonary disease. Although many studies have examined allergic responses to fungi and their effects on pulmonary function, the possible pathologic implications of the early innate responses to fungal pathogens have not been explored. We examined early responses to the atypical fungus Pneumocystis in two common strains of mice in terms of overall immunological response and related pathology, such as cell damage and airway hyperresponsiveness (AHR). We found a strong strain-specific response in BALB/c mice that included recruitment of neutrophils, NK, NKT, and CD4 T cells. This response was accompanied by elevated indicators of lung damage (bronchoalveolar lavage fluid albumin and LDH) and profound AHR. This early response was absent in C57BL/6 mice, although both strains exhibited a later response associated with the clearance of Pneumocystis. We found that this AHR could not be attributed exclusively to the presence of recruited neutrophils, NKT, NK, or CD4 cells or to the actions of IFN-g or IL-4. However, in the absence of STAT6 signaling, AHR and inflammatory cell recruitment were virtually absent. Gene expression analysis indicated that this early response included activation of several transcription factors that could be involved in pulmonary remodeling. These results show that exposure to a fungus such as Pneumocystis can elicit pulmonary responses that may contribute to morbidity, even without prior sensitization, in the context of certain genetic backgrounds.Keywords: STAT6; airway hyperresponsiveness; Pneumocystis; pulmonary inflammation; strain-specificThe immunological response to respiratory pathogens is normally calibrated to eliminate an infection without causing overt collateral damage to the respiratory tissue. In spite of this, an overexuberant or misdirected immune response can have pathological outcomes. This can range from phenomena that are transient and typically moderate, such as elevated airway hyperresponsiveness (AHR), to those that are permanent and progressive, such as pulmonary fibrosis. The health effects of these immunological responses depend on the context of the infection; those that are comorbid with other acute or chronic pulmonary conditions may incite serious respiratory distress in that context when otherwise they might have little noticeable effect.One area in which the effects of comorbid respiratory illnesses are especially relevant is that of exacerbation of preexisting asthma or chronic obstructive pulmonary disease (COPD). Many potential pathogens have been implicated as causing exacerbation; the most well known are various viruses, including rhinovirus, metapneumovirus, and respiratory syncytial virus (1). Several respiratory bacteria, most notably the atypical bacteria Mycoplasma pneumoniae and Chlamydia pneumoniae, have also been implicated in the exacerbation of asthma symptoms (2). Common fungi have also been widely imp...

“…Walker and colleagues (14) reported that CCR5 2/2 mice showed lower AHR, but the numbers of eosinophils in CCR5 2/2 mice were similar to those in CCR5 1/1 mice. In contrast, in the current study, CCR5…”

Section: Sensitized T Cells Obtained From Ccr5mentioning

confidence: 96%

“…Downregulation of CCR5 by a compound and a chemokine ligand suppressed AHR and airway inflammation (12,13). However, it has also been shown that CCR5 regulates the development of AHR, but not eosinophilic inflammation in a mouse model of allergen-induced airway responses (14). Thus, CCR5 might control allergic airway responses, but its role in airway inflammation is controversial.…”

mentioning

confidence: 99%

Requirement for Chemokine Receptor 5 in the Development of Allergen-Induced Airway Hyperresponsiveness and Inflammation

Fuchimoto

Kanehiro

Miyahara

et al. 2011

Chemokine receptor (CCR) 5 is expressed on dendritic cells, macrophages, CD8 cells, memory CD4 T cells, and stromal cells, and is frequently used as a marker of T helper type 1 cells. Interventions that abrogate CCR5 or interfere with its ligand binding have been shown to alter T helper type 2-induced inflammatory responses. The role of CCR5 on allergic airway responses is not defined. CCR5-deficient (CCR5 2/2 ) and wild-type (CCR5 1/1 ) mice were sensitized and challenged with ovalbumin (OVA) and allergic airway responses were monitored 48 hours after the last OVA challenge. Cytokine levels in lung cell culture supernatants were also assessed. CCR5 2/2 mice showed significantly lower airway hyperresponsiveness (AHR) and lower numbers of total cells, eosinophils, and lymphocytes in bronchoalveolar lavage (BAL) fluid compared with CCR51/1 mice after sensitization and challenge. The levels of IL-4 and IL-13 in BAL fluid of CCR5 2/2 mice were lower than in CCR5 1/1 mice. Decreased numbers of lung T cells were also detected in CCR52/2 mice after sensitization and challenge. Transfer of OVAsensitized T cells from CCR5 1/1 , but not transfer of CCR5 2/2 cells, into CCR52/2 mice restored AHR and numbers of eosinophils in BAL fluid after OVA challenge. Accordingly, the numbers of airwayinfiltrating donor T cells were significantly higher in the recipients of CCR5 1/1 T cells. Taken together, these data suggest that CCR5 plays a pivotal role in allergen-induced AHR and airway inflammation, and that CCR5 expression on T cells is essential to the accumulation of these cells in the airways.