The STE20 kinase TAOK3 controls the development of house dust mite–induced asthma in mice,Journal of Allergy and Clinical Immunology

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The STE20 kinase TAOK3 controls the development of house dust mite–induced asthma in mice
Journal of Allergy and Clinical Immunology ( IF 11.4 ) Pub Date : 2021-09-08 , DOI: 10.1016/j.jaci.2021.08.020
Bastiaan Maes ₁ , Ursula Smole ₂ , Matthias Vanderkerken ₂ , Kim Deswarte ₂ , Justine Van Moorleghem ₂ , Karl Vergote ₂ , Manon Vanheerswynghels ₂ , Caroline De Wolf ₂ , Sofie De Prijck ₂ , Nincy Debeuf ₂ , Benjamin Pavie ₃ , Wendy Toussaint ₂ , Sophie Janssens ₄ , Savvas Savvides ₅ , Bart N Lambrecht ₆ , Hamida Hammad ₂

Affiliation

Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium; Laboratory of ER Stress and Inflammation, VIB-UGent Center for Inflammation Research, Ghent, Belgium.
Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.
VIB Bioimaging Core, VIB-UGent Center for Inflammation Research, Ghent, Belgium; Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium; Laboratory of ER Stress and Inflammation, VIB-UGent Center for Inflammation Research, Ghent, Belgium.
Unit for Structural Biology, VIB-UGent Center for Inflammation Research, Ghent, Belgium; Unit for Structural Biology, Department of Biochemistry and Microbiology, Ghent, Belgium.
Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium; Department of Pulmonary Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.

Background

The most common endotype of asthma is type 2–high asthma, which is sometimes driven by adaptive allergen-specific T_H2 lymphocytes that react to allergens presented by dendritic cells (DCs), or sometimes by an innate immune response dominated by type 2 innate lymphocytes (ILC2s). Understanding the underlying pathophysiology of asthma is essential to improve patient-tailored therapy. The STE20 kinase thousand-and-one kinase 3 (TAOK3) controls key features in the biology of DCs and lymphocytes, but to our knowledge, its potential usefulness as a target for asthma therapy has not yet been addressed.

Objective

We examined if and how loss of Taok3 affects the development of house dust mite (HDM)-driven allergic asthma in an in vivo mouse model.

Methods

Wild-type Taok3^+/+ and gene-deficient Taok3^−/− mice were sensitized and challenged with HDM, and bronchoalveolar lavage fluid composition, mediastinal lymph node cytokine production, lung histology, and bronchial hyperreactivity measured. Conditional Taok3^fl/fl mice were crossed to tissue- and cell-specific specific deletor Cre mice to understand how Taok3 acted on asthma susceptibility. Kinase-dead (KD) Taok3^KD mice were generated to probe for the druggability of this pathway. Activation of HDM-specific T cells was measured in adoptively transferred HDM-specific T-cell receptor–transgenic CD4⁺ T cells. ILC2 biology was assessed by in vivo and in vitro IL-33 stimulation assays in Taok3^−/− and Taok3^+/+, Taok3^KD, and Red5-Cre Taok3^fl/fl mice.

Results

Taok3^−/− mice failed to mount salient features of asthma, including airway eosinophilia, T_H2 cytokine production, IgE secretion, airway goblet cell metaplasia, and bronchial hyperreactivity compared to controls. This was due to intrinsic loss of Taok3 in hematopoietic and not epithelial cells. Loss of Taok3 resulted in hampered HDM-induced lung DC migration to the draining lymph nodes and defective priming of HDM-specific T_H2 cells. Strikingly, HDM and IL-33–induced ILC2 proliferation and function were also severely affected in Taok3-deficient and Taok3^KD mice.

Conclusions

Absence of Taok3 or loss of its kinase activity protects from HDM-driven allergic asthma as a result of defects in both adaptive DC-mediated T_H2 activation and innate ILC2 function. This identifies Taok3 as an interesting drug target, justifying further testing as a new treatment for type 2–high asthma.

中文翻译：

STE20 激酶 TAOK3 控制屋尘螨诱发的小鼠哮喘的发展

背景

哮喘最常见的内型是 2 型高哮喘，其有时由对树突状细胞 (DC) 呈递的过敏原作出反应的适应性过敏原特异性 T _H 2 淋巴细胞驱动，或有时由 2 型先天性主导的先天免疫反应驱动淋巴细胞（ILC2）。了解哮喘的潜在病理生理学对于改进针对患者的治疗至关重要。STE20 激酶千零一激酶 3 (TAOK3) 控制 DC 和淋巴细胞生物学的关键特征，但据我们所知，它作为哮喘治疗靶点的潜在用途尚未得到解决。

客观的

我们在体内小鼠模型中检查了Taok3的缺失是否以及如何影响屋尘螨 (HDM) 驱动的过敏性哮喘的发展。

方法

野生型Taok3 ^+/+和基因缺陷型Taok3 ^-/-小鼠用 HDM 致敏和攻击，测量支气管肺泡灌洗液成分、纵隔淋巴结细胞因子产生、肺组织学和支气管高反应性。将条件性 Taok3 ^fl/fl小鼠与组织和细胞特异性缺失基因 Cre 小鼠进行杂交，以了解 Taok3 如何作用于哮喘易感性。生成激酶死亡 (KD) Taok3 ^KD小鼠以探测该途径的成药性。在过继转移的 HDM 特异性 T 细胞受体-转基因 CD4 ⁺ T 细胞中测量了 HDM 特异性 T 细胞的活化。ILC2生物学通过体内评估在Taok3 ^-/-和Taok3 ^+/+、Taok3 ^KD和Red5-Cre Taok3 ^fl/fl小鼠中进行体外IL-33 刺激测定。

结果

与对照组相比， Taok3 ^-/-小鼠未能表现出哮喘的显着特征，包括气道嗜酸性粒细胞增多、TH ₂细胞因子产生、IgE 分泌、气道杯状细胞化生和支气管高反应性。这是由于 Taok3 在造血细胞而非上皮细胞中的内在损失。Taok3 的缺失导致阻碍 HDM 诱导的肺 DC 迁移到引流淋巴结和 HDM 特异性 T _H 2 细胞的启动缺陷。引人注目的是，在 Taok3 缺陷和Taok3 ^KD小鼠中，HDM 和 IL-33 诱导的 ILC2 增殖和功能也受到严重影响。