Identification of an IFN-γ/mast cell axis in a mouse model of chronic asthma
Mang Yu, … , Mindy Tsai, Stephen J. Galli
Mang Yu, … , Mindy Tsai, Stephen J. Galli
Published July 1, 2011
Citation Information: J Clin Invest. 2011;121(8):3133-3143. https://doi.org/10.1172/JCI43598.
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Identification of an IFN-γ/mast cell axis in a mouse model of chronic asthma

Abstract

Asthma is considered a Th2 cell–associated disorder. Despite this, both the Th1 cell–associated cytokine IFN-γ and airway neutrophilia have been implicated in severe asthma. To investigate the relative contributions of different immune system components to the pathogenesis of asthma, we previously developed a model that exhibits several features of severe asthma in humans, including airway neutrophilia and increased lung IFN-γ. In the present studies, we tested the hypothesis that IFN-γ regulates mast cell function in our model of chronic asthma. Engraftment of mast cell–deficient KitW-sh/W-sh mice, which develop markedly attenuated features of disease, with wild-type mast cells restored disease pathology in this model of chronic asthma. However, disease pathology was not fully restored by engraftment with either IFN-γ receptor 1–null (Ifngr1–/–) or Fcε receptor 1γ–null (Fcer1g–/–) mast cells. Additional analysis, including gene array studies, showed that mast cell expression of IFN-γR contributed to the development of many FcεRIγ-dependent and some FcεRIγ-independent features of disease in our model, including airway hyperresponsiveness, neutrophilic and eosinophilic inflammation, airway remodeling, and lung expression of several cytokines, chemokines, and markers of an alternatively activated macrophage response. These findings identify a previously unsuspected IFN-γ/mast cell axis in the pathology of chronic allergic inflammation of the airways in mice.

Authors

Mang Yu, Michael R. Eckart, Alexander A. Morgan, Kaori Mukai, Atul J. Butte, Mindy Tsai, Stephen J. Galli

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Figure 2

Influence of IFN-γ on the expression of mast cell function in vitro.

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Influence of IFN-γ on the expression of mast cell function in vitro. Cul...
Culture supernatants of anti-DNP IgE-sensitized BMCMCs from WT C57BL/6 (black bars), Ifngr1–/– (white bars), or Fcer1g–/– (gray bars) mice were collected 1 hour (for calculation of % histamine release) or 24 hours (for measurement of secreted cytokines) after addition of DNP-HSA or DNP/IFN-γ. Data were calculated from results pooled from 3 independent experiments, each of which gave similar results. IL-6 levels in supernatants collected from the cultures of WT BMCMCs stimulated with 1 or 5 ng/ml of IFN-γ in the absence of DNP-HSA were 0.009 ± 0.002 or 0.007 ± 0.002 ng/ml; the corresponding IL-13 levels were 0.015 ± 0.003 or 0.018 ± 0.004 ng/ml, respectively. *P < 0.05, **P < 0.01, §P < 0.001 versus values from the corresponding BMCMCs stimulated with 1 ng/ml DNP-HSA alone. †P < 0.05, ††P < 0.01, †††P < 0.001 versus group indicated. ‡P < 0.05, ‡‡P < 0.01, #P < 0.001 versus values from the corresponding BMCMCs stimulated with 10 ng/ml DNP-HSA alone. n = 3 per group.