Cannabinoid receptor 2 engagement promotes group 2 innate lymphoid cell expansion and enhances airway hyperreactivity.
Cannabinoid receptor 2 engagement promotes group 2 innate lymphoid cell expansion and enhances airway hyperreactivity.
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大麻素受体2的激活可促进2型天然淋巴细胞扩增并加剧气道高反应性。
DOI：
10.1016/j.jaci.2021.09.037
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发表时间：
2022-05
影响因子：
14.2
通讯作者：
Akbari, Omid
中科院分区：
文献类型：
--
作者：
Hurrell, Benjamin P.;Helou, Doumet Georges;Shafiei-Jahani, Pedram;Howard, Emily;Painter, Jacob D.;Quach, Christine;Akbari, Omid
大麻素调节肺部免疫细胞和生理过程的激活。第2组先天淋巴细胞（ILC 2）是2型哮喘的核心参与者，但大麻素如何调节ILC 2激活仍有待阐明。我们的目标是研究大麻素对ILC 2的影响及其在哮喘中的作用。大麻素受体（CB）2 KO小鼠、CB 2拮抗剂和激动剂的组合用于IL-33、IL-25和链格孢菌（Alternaria alternata）ILC 2依赖性气道炎症的小鼠模型中，并进行RNA测序以评估ILC 2中的转录组学变化。人源化小鼠用于评估CB 2信号传导在人ILC 2中的作用。我们在这里提供的证据表明，在ILC 2中的CB 2信号传导对于小鼠和人类ILC 2驱动的气道炎症的发展是重要的。我们发现，幼稚和活化的小鼠肺ILC 2表达CB 2。CB 2信号传导在稳态下不影响ILC 2稳态，但在活化后显著刺激ILC 2增殖和功能。因此，缺乏CB 2的ILC 2诱导较低的肺部炎症，因为我们使用CB 2拮抗剂进行了类似的观察。相反，CB 2激动显著加剧ILC 2驱动的气道高反应性和肺部炎症。转录组学和蛋白质分析揭示，CB 2信号传导诱导ILC 2中CREB磷酸化。人ILC 2表达CB 2，因为CB 2拮抗和激动作用对ILC 2效应子功能和人源化小鼠中气道高反应性的发展显示出相反的作用。总的来说，我们的研究结果将ILC 2中的CB 2信号传导定义为气道炎症的重要调节剂。我们的研究结果强调了大麻素对ILC 2的刺激能力，并提供了新的治疗途径，包括使用能够调节CB 2的物质或途径，从而减轻肺部炎症患者的肺功能。这项研究首次强调了CB 2信号在促进ILC 2依赖性气道炎症中的作用，为开发新的适应性治疗策略开辟了途径。
Cannabinoids modulate the activation of immune cells and physiological processes in the lungs. Group-2 innate lymphoid cells (ILC2)s are central players in type-2 asthma, but how cannabinoids modulate ILC2 activation remains to be elucidated Our goal is to investigate the effects of cannabinoids on ILC2s and their role in asthma. A combination of Cannabinoid receptor (CB)2 KO mice, CB2 antagonist and agonist were used in the mouse models of IL-33, IL-25 and Alternaria alternata ILC2-dependent airway inflammation, and RNA sequencing was performed to assess transcriptomic changes in ILC2s. Humanized mice were used to assess the role of CB2 signaling in human ILC2s. We here provide evidence that CB2 signaling in ILC2s is important for the development of ILC2-driven airway inflammation in both mice and human. We showed that both naïve and activated murine pulmonary ILC2s express CB2. CB2 signaling did not affect ILC2 homeostasis at steady state, but strikingly stimulated ILC2 proliferation and function upon activation. As a result, ILC2s lacking CB2 induced lower lung inflammation, as we made similar observations using a CB2 antagonist. Conversely, CB2 agonism remarkably exacerbated ILC2-driven airway hyperreactivity and lung inflammation. Mechanistically, transcriptomic and protein analysis revealed that CB2 signaling induced CREB phosphorylation in ILC2s. Human ILC2s expressed CB2, as CB2 antagonism and agonism showed opposing effects on ILC2 effector function and development of airway hyperreactivity in humanized mice. Collectively, our results define CB2 signaling in ILC2s as an important modulator of airway inflammation. Our findings highlight the stimulatory capacity of cannabinoids on ILC2s and offer new therapeutic avenues, including the use of substances or pathways able to modulate CB2 capable of alleviating lung function in patients with lung inflammation. This study is the first to highlight the role of CB2 signaling in promoting ILC2-dependent airway inflammation, opening avenues for the development of novel adapted therapeutic strategies.
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影响因子：
3.7
作者：
Basu S;Ray A;Dittel BN
通讯作者：
Dittel BN
影响因子：
12.4
作者：
Ferrini ME;Hong S;Stierle A;Stierle D;Stella N;Roberts K;Jaffar Z
通讯作者：
Jaffar Z
影响因子：
4.8
作者：
D'Argenio, G;Valenti, M;Di Marzo, V
通讯作者：
Di Marzo, V
人体免疫组织和白细胞亚群中枢和外周大麻素受体的表达
DOI：
10.1111/j.1432-1033.1995.tb20780.x
发表时间：
1995-08-15
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
GALIEGUE, S;MARY, S;CASELLAS, P
通讯作者：
CASELLAS, P
影响因子：
2.8
作者：
Braun, Andrea;Engel, Tabea;Mempel, Martin
通讯作者：
Mempel, Martin