Role of mast cells, eosinophils and IL‐5 in the development of airway hyperresponsiveness in sensitized mice

We have studied murine models of asthma using FcεRIα-chain-deficient (FcεRIα−/−) mice to investigate the role of IgE-dependent mast cell activation in these models. When mice were either 1) immunized once with OVA in alum i.p. and then challenged with OVA intranasally, or 2) repeatedly immunized with OVA in the absence of adjuvant and subsequently challenged with nebulized OVA, FcεRα−/− mice had significantly fewer eosinophils and lower IL-4 levels in their bronchoalveolar lavage fluid compared with wild-type mice. When mice were given anti-IL-5 antibody before OVA challenge in protocol 1, eosinophilic infiltration into the airways was significantly suppressed in both genotypes, but only FcεRIα−/− mice showed significantly reduced airway hyperresponsiveness (AHR). In addition, when mice immunized and challenged with OVA also received a late OVA provocation at a higher concentration and were then exposed to methacholine, only wild-type mice developed a substantial increase in AHR. Since FcεRI is expressed mainly on mast cells in mouse airways, we conclude that IgE-dependent activation of this cell type plays an important role in the development of allergic airway inflammation and AHR in mice. The models used may be of value for testing inhibitors of IgE or mast cells for development of therapeutic agents for human asthma.

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

IgE-Dependent Mast Cell Activation Potentiates Airway Responses in Murine Asthma Models

Mayr

Zuberi

Zhang

et al. 2002

“…When studying mechanisms of allergic airway disease in animal models, mast cell-deficient mice have variable decreases in eosinophil numbers (31,32) following allergen challenge, but systemically sensitized and challenged mast cell-deficient mice are capable of developing a Th2 response, airway inflammation, and AHR similar to WT control mice (33)(34)(35)(36). In most of these studies, allergen sensitization was achieved by systemically injecting the allergen in combination with an adjuvant, while other studies, using less potent sensitization protocols, demonstrated a more obvious role for mast cells in the development of AHR (37,38).…”

Section: Discussionmentioning

confidence: 99%

The Leukotriene B4 Receptor (BLT1) Is Required for Effector CD8+ T Cell-Mediated, Mast Cell-Dependent Airway Hyperresponsiveness

Taube

Miyahara

Ott

et al. 2006

Studies in both humans and rodents have suggested that CD8+ T cells contribute to the development of airway hyperresponsiveness (AHR) and that leukotriene B4 (LTB4) is involved in the chemotaxis of effector CD8+ T cells (TEFF) to the lung by virtue of their expression of BLT1, the receptor for LTB4. In the present study, we used a mast cell-CD8-dependent model of AHR to further define the role of BLT1 in CD8+ T cell-mediated AHR. C57BL/6+/+ and CD8-deficient (CD8−/−) mice were passively sensitized with anti-OVA IgE and exposed to OVA via the airways. Following passive sensitization and allergen exposure, C57BL/6+/+ mice developed altered airway function, whereas passively sensitized and allergen-exposed CD8−/− mice failed to do so. CD8−/− mice reconstituted with CD8+ TEFF developed AHR in response to challenge. In contrast, CD8−/− mice reconstituted with BLT1-deficient effector CD8+ T cells did not develop AHR. The induction of increased airway responsiveness following transfer of CD8+ TEFF or in wild-type mice could be blocked by administration of an LTB4 receptor antagonist confirming the role of BLT1 in CD8+ T cell-mediated AHR. Together, these data define the important role for mast cells and the LTB4-BLT1 pathway in the development of CD8+ T cell-mediated allergic responses in the lung.

“…However, the role of mast cells in the development of AHR is somewhat controversial. When studying mechanisms of allergic airway disease in animals models, mast cell-deficient mice have variable decreases in eosinophil numbers (10,11) after allergen challenge, but systemically sensitized and challenged mast cell-deficient mice are capable of developing a Th2 response, airway inflammation, and AHR similar to wild-type control mice (12)(13)(14)(15). In most of these studies allergen sensitization was achieved by systemically injecting the allergen in combination with an adjuvant, whereas other studies, using less potent sensitization protocols, demonstrated a more obvious role for mast cells in the development of AHR (16,17).…”

mentioning

confidence: 99%

Mast Cells, FcεRI, and IL-13 Are Required for Development of Airway Hyperresponsiveness after Aerosolized Allergen Exposure in the Absence of Adjuvant

Taube

Wei

Swasey

et al. 2004

106

In certain models of allergic airway disease, mast cells facilitate the development of inflammation and airway hyper-responsiveness (AHR). To define the role of the high affinity IgE receptor (FcεRI) in the development of AHR, mice with a disruption of the α subunit of the high affinity IgE receptor (FcεRI−/−) were exposed on 10 consecutive days to nebulized OVA. Forty-eight hours after the last nebulization, airway responsiveness was monitored by the contractile response of tracheal smooth muscle to electrical field stimulation (EFS). After the 10-day OVA challenge protocol, wild-type mice demonstrated increased responsiveness to EFS, whereas similarly challenged FcεRI−/− mice showed a low response to EFS, similar to nonexposed animals. Further, allergen-challenged FcεRI−/− mice showed less airway inflammation, goblet cell hyperplasia, and lower levels of IL-13 in lung homogenates compared with the controls. IL-13-deficient mice failed to develop an increased response to EFS or goblet cell hyperplasia after the 10-day OVA challenge. We transferred bone marrow-derived mast cells from wild-type mice to FcεRI−/− mice 1 day before initiating the challenge protocol. After the 10-day OVA challenge, recipient FcεRI−/− mice demonstrated EFS-induced responses similar to those of challenged wild-type mice. Transferred mast cells could be detected in tracheal preparations. These results show that FcεRI is important for the development of AHR after an aerosolized allergen sensitization protocol and that this effect is mediated through FcεRI on mast cells and production of IL-13 in the lung.