A humanized mouse model to study asthmatic airway inflammation via the human IL-33/IL-13 axis
Ryoji Ito, … , Mamoru Ito, Satoshi Nunomura
Ryoji Ito, … , Mamoru Ito, Satoshi Nunomura
Published November 2, 2018
Citation Information: JCI Insight. 2018;3(21):e121580. https://doi.org/10.1172/jci.insight.121580.
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Resource and Technical Advance Immunology Inflammation

A humanized mouse model to study asthmatic airway inflammation via the human IL-33/IL-13 axis

Abstract

Asthma is one of the most common immunological diseases and is characterized by airway hyperresponsiveness (AHR), mucus overproduction, and airway eosinophilia. Although mouse models have provided insight into the mechanisms by which type-2 cytokines induce asthmatic airway inflammation, differences between the rodent and human immune systems hamper efforts to improve understanding of human allergic diseases. In this study, we aim to establish a preclinical animal model of asthmatic airway inflammation using humanized IL-3/GM-CSF or IL-3/GM-CSF/IL-5 Tg NOD/Shi-scid-IL2rγnull (NOG) mice and investigate the roles of human type-2 immune responses in the asthmatic mice. Several important characteristics of asthma — such as AHR, goblet cell hyperplasia, T cell infiltration, IL-13 production, and periostin secretion — were induced in IL-3/GM-CSF Tg mice by intratracheally administered human IL-33. In addition to these characteristics, human eosinophilic inflammation was observed in IL-3/GM-CSF/IL-5 Tg mice. The asthmatic mechanisms of the humanized mice were driven by activation of human Th2 and mast cells by IL-33 stimulation. Furthermore, treatment of the humanized mice with an anti–human IL-13 antibody significantly suppressed these characteristics. Therefore, the humanized mice may enhance our understanding of the pathophysiology of allergic disorders and facilitate the preclinical development of new therapeutics for IL-33–mediated type-2 inflammation in asthma.

Authors

Ryoji Ito, Shuichiro Maruoka, Kaori Soda, Ikumi Katano, Kenji Kawai, Mika Yagoto, Asami Hanazawa, Takeshi Takahashi, Tomoyuki Ogura, Motohito Goto, Riichi Takahashi, Shota Toyoshima, Yoshimichi Okayama, Kenji Izuhara, Yasuhiro Gon, Shu Hashimoto, Mamoru Ito, Satoshi Nunomura

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Figure 3

Asthma characteristics in IL-33–treated hu–IL-3/GM Tg mice.

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Asthma characteristics in IL-33–treated hu–IL-3/GM Tg mice. (A) Images o...
(A) Images of murine goblet cells in the lungs of hu–non-Tg and hu–IL-3/GM Tg mice administered saline or IL-33 and stained by Alcian Blue–Periodic acid-Schiff (AB-PAS). (B) Enumeration of PAS-positive goblet cells in the lungs. HPF, high-power field. (C) Murine periostin levels in BALF were measured by ELISA. (D) IHC of periostin. Lung sections from hu–non-Tg and Tg mice with or without IL-33 treatment were stained with anti–mouse periostin or its isotype control. Representative data from each 4 or 5 mice/group are shown. Red-outline represents that periostine was positively stained. (E) Relationship between IL-13 (x axis) and periostin (y axis) and IL-5 (x axis) and periostin (y axis) levels in the BALF of Tg mice treated with saline (n = 6) or IL-33 (n = 5). (F) Mice received increasing doses of methacholine as indicated. Airway resistance (R) after human IL-33 or saline treatment was measured using the FinePointe airway resistance analysis system. Three hu–non-Tg mice and 6 hu–IL-3/GM Tg mice were used. (G) Relationship between IL-5 (x axis) and airway resistance (R) (y axis) in the BALF of Tg mice treated with IL-33. Data are represented 3–6 mice in each group. Original magnification, ×10 or ×40 in (A); ×10 in (D). Scale bar: 50 μm or 10 μm in (A); 100 μm in (D). *P < 0.05 and **P < 0.005 compared with saline-treated groups. Statistical significance was calculated using Student’s t test (F) and 1-way ANOVA (B and C). Pearson’s correlation coefficient (R2) was used to assess correlations (E and G).