阻断CD226调节ILC2功能并减轻气道高反应性
2024/02/23
摘要
背景：2型固有淋巴细胞（ILC2）在2型哮喘中起着关键作用。CD226是一种参与多种炎症性疾病的共刺激分子。
目的：我们旨在研究CD226在人和小鼠ILC2中的表达和功能，并评估靶向CD226对ILC2介导的气道高反应性（AHR）的影响。
方法：我们对野生型小鼠鼻内给予IL-33，然后用抗CD226抗体或同种型对照进行治疗。通过RNA测序和流式细胞术对肺ILC2进行分类以进行离体分析。接下来，我们评估了CD226对野生型和Rag2小鼠的AHR和肺部炎症的影响。此外，我们比较了来自健康供体和哮喘患者的外周ILC2，以确定CD226在人ILC2中的作用。-/-
结果：我们的研究结果表明，CD226在活化的ILC2中可诱导表达，增强其细胞因子分泌和功能。从机制上讲，CD226改变细胞内代谢并增强PI3K/AKT和MAPK信号通路。阻断CD226改善IL-33和链格孢霉属诱导的模型中的ILC2依赖性AHR。有趣的是，CD226在人ILC2中表达和诱导，其阻断可减少细胞因子的产生。最后，我们发现，与健康对照组相比，哮喘患者的外周ILC2表现出CD226表达升高。
结论：我们的研究结果强调了CD226作为ILC2新治疗靶点的潜力，为改善AHR和过敏性哮喘提供了一条有希望的途径。
Blocking CD226 regulates ILC2 effector function and alleviates airway hyperreactivity
Yoshihiro Sakano, Kei Sakano, Benjamin P Hurrell, Doumet Georges Helou, Pedram Shafiei-Jahani, Mohammad H Kazemi, Xin Li, Stephen Shen, James R Hilser, Jaana A Hartiala, Hooman Allayee, Richard Barbers, Omid Akbari
Abstract
Background: Type 2 innate lymphoid cells (ILC2s) play a pivotal role in type 2 asthma. CD226 is a costimulatory molecule involved in various inflammatory diseases.
Objective: We aimed to investigate CD226 expression and function within human and mouse ILC2s, and to assess the impact of targeting CD226 on ILC2-mediated airway hyperreactivity (AHR).
Methods: We administered IL-33 intranasally to wild-type mice, followed by treatment with anti-CD226 antibody or isotype control. Pulmonary ILC2s were sorted for ex vivo analyses through RNA sequencing and flow cytometry. Next, we evaluated the effects of CD226 on AHR and lung inflammation in wild-type and Rag2 mice. Additionally, we compared peripheral ILC2s from healthy donors and asthmatic patients to ascertain the role of CD226 in human ILC2s. -/-
Results: Our findings demonstrated an inducible expression of CD226 in activated ILC2s, enhancing their cytokine secretion and effector functions. Mechanistically, CD226 alters intracellular metabolism and enhances PI3K/AKT and MAPK signal pathways. Blocking CD226 ameliorates ILC2-dependent AHR in IL-33 and Alternaria Alternata-induced models. Interestingly, CD226 is expressed and inducible in human ILC2s, and its blocking reduces cytokine production. Finally, we showed that peripheral ILC2s in asthmatic patients exhibited elevated CD226 expression compared to healthy controls.
Conclusion: Our findings underscore the potential of CD226 as a novel therapeutic target in ILC2s, presenting a promising avenue for ameliorating AHR and allergic asthma.
背景：2型固有淋巴细胞（ILC2）在2型哮喘中起着关键作用。CD226是一种参与多种炎症性疾病的共刺激分子。
目的：我们旨在研究CD226在人和小鼠ILC2中的表达和功能，并评估靶向CD226对ILC2介导的气道高反应性（AHR）的影响。
方法：我们对野生型小鼠鼻内给予IL-33，然后用抗CD226抗体或同种型对照进行治疗。通过RNA测序和流式细胞术对肺ILC2进行分类以进行离体分析。接下来，我们评估了CD226对野生型和Rag2小鼠的AHR和肺部炎症的影响。此外，我们比较了来自健康供体和哮喘患者的外周ILC2，以确定CD226在人ILC2中的作用。-/-
结果：我们的研究结果表明，CD226在活化的ILC2中可诱导表达，增强其细胞因子分泌和功能。从机制上讲，CD226改变细胞内代谢并增强PI3K/AKT和MAPK信号通路。阻断CD226改善IL-33和链格孢霉属诱导的模型中的ILC2依赖性AHR。有趣的是，CD226在人ILC2中表达和诱导，其阻断可减少细胞因子的产生。最后，我们发现，与健康对照组相比，哮喘患者的外周ILC2表现出CD226表达升高。
结论：我们的研究结果强调了CD226作为ILC2新治疗靶点的潜力，为改善AHR和过敏性哮喘提供了一条有希望的途径。
(中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校)
(J Allergy Clin Immunol. 2024 Jan 18:S0091-6749(24)00035-6. doi: 10.1016/j.jaci.2024.01.003.)
(J Allergy Clin Immunol. 2024 Jan 18:S0091-6749(24)00035-6. doi: 10.1016/j.jaci.2024.01.003.)
Blocking CD226 regulates ILC2 effector function and alleviates airway hyperreactivity
Yoshihiro Sakano, Kei Sakano, Benjamin P Hurrell, Doumet Georges Helou, Pedram Shafiei-Jahani, Mohammad H Kazemi, Xin Li, Stephen Shen, James R Hilser, Jaana A Hartiala, Hooman Allayee, Richard Barbers, Omid Akbari
Abstract
Background: Type 2 innate lymphoid cells (ILC2s) play a pivotal role in type 2 asthma. CD226 is a costimulatory molecule involved in various inflammatory diseases.
Objective: We aimed to investigate CD226 expression and function within human and mouse ILC2s, and to assess the impact of targeting CD226 on ILC2-mediated airway hyperreactivity (AHR).
Methods: We administered IL-33 intranasally to wild-type mice, followed by treatment with anti-CD226 antibody or isotype control. Pulmonary ILC2s were sorted for ex vivo analyses through RNA sequencing and flow cytometry. Next, we evaluated the effects of CD226 on AHR and lung inflammation in wild-type and Rag2 mice. Additionally, we compared peripheral ILC2s from healthy donors and asthmatic patients to ascertain the role of CD226 in human ILC2s. -/-
Results: Our findings demonstrated an inducible expression of CD226 in activated ILC2s, enhancing their cytokine secretion and effector functions. Mechanistically, CD226 alters intracellular metabolism and enhances PI3K/AKT and MAPK signal pathways. Blocking CD226 ameliorates ILC2-dependent AHR in IL-33 and Alternaria Alternata-induced models. Interestingly, CD226 is expressed and inducible in human ILC2s, and its blocking reduces cytokine production. Finally, we showed that peripheral ILC2s in asthmatic patients exhibited elevated CD226 expression compared to healthy controls.
Conclusion: Our findings underscore the potential of CD226 as a novel therapeutic target in ILC2s, presenting a promising avenue for ameliorating AHR and allergic asthma.
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