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

Abstract

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.

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

“…1). These data extend our previous findings (19) and identify an IgEFc⑀RI-mast cell-CD8 pathway in the development of altered airway reactivity in this passive sensitization and allergen challenge model.…”

“…In a comparable model of mast cell-dependent development of AHR, IL-13 was shown to be essential (19). In the passive sensitization model, development of altered tracheal smooth muscle reactivity was shown to be dependent on IL-13: IL-13-deficient mice failed to develop increased reactivity when passively sensitized and challenged when compared with WT mice (Fig.…”

“…We previously suggested that the failure of mast cell-deficient mice or Fc⑀RI Ϫ/Ϫ mice to develop AHR in a similar system could be overcome by adoptive transfer of bone marrow-derived mast cells from WT or IL-13 Ϫ/Ϫ mice (19) and that the failure of CD8 Ϫ/Ϫ mice to respond could be overcome by IL-13 ϩ/ϩ but not IL-13 Ϫ/Ϫ CD8 T cells (7). These data suggested that activated mast cells were critical to the recruitment of CD8 ϩ T cells and BLT1-expressing CD8 T cells.…”

“…This model of AHR is similar to repeated inhaled allergen exposure which is known to be dependent on mast cells, expression of Fc⑀RI, and IL-13 (19). This mast cell-dependent model, which bypasses the need for host-derived IgE, was used to define the functional properties of memory CD8 ϩ T cells, especially T EFF cells, as well as their dependence on BLT1 expression.…”

Increased IgE but Reduced Th2-Type Inflammation in Vitamin D Receptor-Deficient Mice

“…We therefore think it unlikely that IgE receptor blocking plays a role in the reduced AHR we observed in the VDR null mice. By contrast, more recent studies suggest that inducing airways hyperresponsiveness in the absence of adjuvant does require IgE, high affinity Fc⑀R, and mast cells in mice (7). Finally, as Dr. D'Ambrosio pointed out (in the paper by Yazdanbakhsh et al) there are numerous examples of situations where elevated baseline IgE does not result in asthma and many possible mechanistic explanations.…”