白细胞介素-2 家族细胞因子 IL-9 和 IL-21 对哮喘的先天性和适应性 2 型免疫有不同的调节作用
2024/08/28
摘要
背景：哮喘通常伴随着由 TH2 淋巴细胞或 2 型先天性淋巴细胞（ILC2s）产生的富含 IL-4、IL-5 和 IL-13 细胞因子的 2 型免疫。白细胞介素-2 家族细胞因子在先天性和适应性淋巴细胞的分化、平衡和效应功能中发挥着关键作用。IL-9 和 IL-21 可促进 TH2 和 ILC2 的活化和增殖，但这些 γc 细胞因子的相对重要性和潜在协同作用目前尚不清楚。
方法：利用新生成的抗体，我们在各种哮喘小鼠模型中单独或联合抑制了 IL-9 和 IL-21。最近，我们利用分段过敏原挑战的转化方法描述了与非哮喘对照组相比，人类过敏性哮喘患者体内 IL-9 水平的升高。在这里，我们还测量了两组患者的 IL-21。
结果：IL-9通过促进ILC2的增殖和活化，在控制先天性IL-33诱导的肺部炎症中发挥着核心作用，其方式与IL-21无关。相反，主要由适应性免疫驱动的慢性屋尘螨诱导的气道炎症则完全依赖于 IL-21，它控制着 TH2 的活化、嗜酸性粒细胞增多、血清 IgE 总量和三级淋巴结构的形成。在一个由木瓜蛋白酶过敏原驱动的先天性和适应性免疫模型中，发现这两种途径之间有明显的协同作用，因为联合阻断抗IL-9或抗IL-21能更好地减少哮喘的主要特征。在人体支气管肺泡灌洗液（BAL）样本中，我们测得过敏性哮喘组的 IL-21 蛋白高于过敏性对照组。我们还发现在各种疾病相关细胞亚群中，IL21R 转录物和预测的 IL-21 配体活性都有所增加。
结论：IL-9和IL-21通过增强ILC2和TH2细胞在过敏性哮喘中发挥着重要而非多余的作用，揭示了IL-9和IL-21双重靶向策略是一种新的可测试方法。
Interleukin-2 family cytokines IL-9 and IL-21 differentially regulate innate and adaptive type 2 immunity in asthma
Bick F, Brenis Gómez CM, Lammens I, Van Moorleghem J, De Wolf C, Dupont S, Dumoutier L, Smith NP, Villani AC, Browaeys R, Alladina J, Haring AM, Medoff BD, Cho JL, Bigirimana R, Vieira J, Hammad H, Blanchetot C, Schuijs MJ, Lambrecht BN.
Abstract
Background:Asthma is often accompanied by type 2 immunity rich in IL-4, IL-5 and IL-13 cytokines produced by TH2 lymphocytes or type 2 innate lymphoid cells (ILC2s). Interleukin-2 family cytokines play a key role in the differentiation, homeostasis and effector function of innate and adaptive lymphocytes. IL-9 and IL-21 boost the activation and proliferation of TH2 and ILC2s, but the relative importance and potential synergism between these γc cytokines is currently unknown.
Methods:Using newly generated antibodies, we inhibited IL-9 and IL-21 alone or in combination, in various murine models of asthma. In a translational approach using segmental allergen challenge, we recently described elevated IL-9 levels in human allergic asthmatics in comparison to non-asthmatic controls. Here, we also measured IL-21 in both groups.
Results:IL-9 played a central role in controlling innate IL-33 induced lung inflammation by promoting proliferation and activation of ILC2s, in an IL-21 independent manner. Conversely, chronic house dust mite induced airway inflammation, mainly driven by adaptive immunity, was solely dependent on IL-21, that controlled TH2 activation, eosinophilia, total serum IgE and formation of tertiary lymphoid structures. In a model of innate on adaptive immunity driven by papain allergen, a clear synergy was found between both pathways, since combined anti-IL-9 or anti-IL-21 blockade was superior in reducing key asthma features. In human bronchoalveolar lavage (BAL) samples we measured elevated IL-21 protein within the allergic asthmatic group, compared with the allergic control group. We also found increased IL21R transcripts and predicted IL-21 ligand activity in various disease-associated cell subsets.
Conclusion:IL-9 and IL-21 play important and non-redundant roles in allergic asthma by boosting ILC2s and TH2 cells, revealing a dual IL-9 and IL-21 targeting strategy as a new and testable approach.
背景：哮喘通常伴随着由 TH2 淋巴细胞或 2 型先天性淋巴细胞（ILC2s）产生的富含 IL-4、IL-5 和 IL-13 细胞因子的 2 型免疫。白细胞介素-2 家族细胞因子在先天性和适应性淋巴细胞的分化、平衡和效应功能中发挥着关键作用。IL-9 和 IL-21 可促进 TH2 和 ILC2 的活化和增殖，但这些 γc 细胞因子的相对重要性和潜在协同作用目前尚不清楚。
方法：利用新生成的抗体，我们在各种哮喘小鼠模型中单独或联合抑制了 IL-9 和 IL-21。最近，我们利用分段过敏原挑战的转化方法描述了与非哮喘对照组相比，人类过敏性哮喘患者体内 IL-9 水平的升高。在这里，我们还测量了两组患者的 IL-21。
结果：IL-9通过促进ILC2的增殖和活化，在控制先天性IL-33诱导的肺部炎症中发挥着核心作用，其方式与IL-21无关。相反，主要由适应性免疫驱动的慢性屋尘螨诱导的气道炎症则完全依赖于 IL-21，它控制着 TH2 的活化、嗜酸性粒细胞增多、血清 IgE 总量和三级淋巴结构的形成。在一个由木瓜蛋白酶过敏原驱动的先天性和适应性免疫模型中，发现这两种途径之间有明显的协同作用，因为联合阻断抗IL-9或抗IL-21能更好地减少哮喘的主要特征。在人体支气管肺泡灌洗液（BAL）样本中，我们测得过敏性哮喘组的 IL-21 蛋白高于过敏性对照组。我们还发现在各种疾病相关细胞亚群中，IL21R 转录物和预测的 IL-21 配体活性都有所增加。
结论：IL-9和IL-21通过增强ILC2和TH2细胞在过敏性哮喘中发挥着重要而非多余的作用，揭示了IL-9和IL-21双重靶向策略是一种新的可测试方法。
(中日友好医院呼吸与危重症医学科 沈焜路 摘译 林江涛 审校)
(J Allergy Clin Immunol. 2024 Aug 13; DOI: 10.1016/j.jaci.2024.07.024)
(J Allergy Clin Immunol. 2024 Aug 13; DOI: 10.1016/j.jaci.2024.07.024)
Interleukin-2 family cytokines IL-9 and IL-21 differentially regulate innate and adaptive type 2 immunity in asthma
Bick F, Brenis Gómez CM, Lammens I, Van Moorleghem J, De Wolf C, Dupont S, Dumoutier L, Smith NP, Villani AC, Browaeys R, Alladina J, Haring AM, Medoff BD, Cho JL, Bigirimana R, Vieira J, Hammad H, Blanchetot C, Schuijs MJ, Lambrecht BN.
Abstract
Background:Asthma is often accompanied by type 2 immunity rich in IL-4, IL-5 and IL-13 cytokines produced by TH2 lymphocytes or type 2 innate lymphoid cells (ILC2s). Interleukin-2 family cytokines play a key role in the differentiation, homeostasis and effector function of innate and adaptive lymphocytes. IL-9 and IL-21 boost the activation and proliferation of TH2 and ILC2s, but the relative importance and potential synergism between these γc cytokines is currently unknown.
Methods:Using newly generated antibodies, we inhibited IL-9 and IL-21 alone or in combination, in various murine models of asthma. In a translational approach using segmental allergen challenge, we recently described elevated IL-9 levels in human allergic asthmatics in comparison to non-asthmatic controls. Here, we also measured IL-21 in both groups.
Results:IL-9 played a central role in controlling innate IL-33 induced lung inflammation by promoting proliferation and activation of ILC2s, in an IL-21 independent manner. Conversely, chronic house dust mite induced airway inflammation, mainly driven by adaptive immunity, was solely dependent on IL-21, that controlled TH2 activation, eosinophilia, total serum IgE and formation of tertiary lymphoid structures. In a model of innate on adaptive immunity driven by papain allergen, a clear synergy was found between both pathways, since combined anti-IL-9 or anti-IL-21 blockade was superior in reducing key asthma features. In human bronchoalveolar lavage (BAL) samples we measured elevated IL-21 protein within the allergic asthmatic group, compared with the allergic control group. We also found increased IL21R transcripts and predicted IL-21 ligand activity in various disease-associated cell subsets.
Conclusion:IL-9 and IL-21 play important and non-redundant roles in allergic asthma by boosting ILC2s and TH2 cells, revealing a dual IL-9 and IL-21 targeting strategy as a new and testable approach.
上一篇：
哮喘气道炎症期间的突显网络静息态功能连接度： 心理健康韧性的特征？
下一篇：
局部受体相互作用蛋白激酶2抑制减轻HDM诱导的哮喘
