A20是巨噬细胞中IL-33信号传导的主开关，并决定IL-33诱导的肺部免疫
2023/04/21
摘要
背景：IL-33在哮喘和特应性皮炎等过敏性疾病的发病机制中起着重要作用。从肺上皮细胞释放后，IL-33主要驱动2型免疫反应，伴有嗜酸性粒细胞增多和IL-4、IL-5和IL-13的大量产生。然而，几项研究表明，IL-33也可以驱动1型免疫反应。
目的：关于IL-33是否诱导1型或2型免疫反应的机制仍存在重要问题。在这里，我们重点关注A20在巨噬细胞中IL-33信号传导的调节和IL-33诱导的肺免疫中的作用。
方法：我们研究了IL-33处理的小鼠肺部的免疫反应，这些小鼠的骨髓细胞中特异性缺乏A20。我们还分析了A20缺陷骨髓来源的巨噬细胞中的IL-33信号传导。
结果：在巨噬细胞A20不表达的情况下，IL-33诱导的肺ILC2扩张、2型细胞因子产生和嗜酸性粒细胞增多显著减少，而肺中的中性粒细胞和间质巨噬细胞增加。在体外，IL-33介导的NF-κB活化仅在A20缺陷巨噬细胞中受到微弱影响。然而，在缺乏A20的情况下，IL-33获得了激活STAT1信号传导和STAT1依赖性基因表达的能力。令人惊讶的是，A20缺陷的巨噬细胞对IL-33产生IFN-γ，IL-33完全依赖于STAT1。此外，STAT1缺乏部分恢复了IL-33在髓细胞特异性A20敲除小鼠中诱导ILC2扩增和嗜酸性粒细胞增多的能力。
结论：我们揭示了A20作为IL-33诱导的巨噬细胞STAT1信号传导和IFN-γ产生的负调节因子的新作用，IFN-γ的产生决定了肺免疫反应。
临床意义：我们的研究结果可能最终有助于确定更好地对患者进行分层的策略，从而提高治疗效果。
A20 is a master switch of IL-33 signalling in macrophages and determines IL-33-induced lung immunity
Aurora Holgado, Zhuangzhuang Liu, Aigerim Aidarova, Christina Mueller, Mira Haegman, Yasmine Driege, Marja Kreike, Charlotte L Scott, Inna S Afonina, Rudi Beyaert
Abstract
Background: IL-33 plays a major role in the pathogenesis of allergic diseases such as asthma and atopic dermatitis. Upon its release from lung epithelial cells, IL-33 primarily drives type 2 immune responses, accompanied by eosinophilia and robust production of IL-4, IL-5 and IL-13. However, several studies show that IL-33 can also drive a type 1 immune response.
Objective: Important questions remain regarding the mechanisms that determine whether IL-33 induces a type 1 or type 2 immune response. Here we focus on the role of A20 in the regulation of IL-33 signalling in macrophages and IL-33-induced lung immunity.
Methods: We studied the immunological response in lungs of IL-33-treated mice that specifically lack A20 in myeloid cells. We also analysed IL-33 signalling in A20-deficient bone marrow derived macrophages.
Results: IL-33-induced lung ILC2 expansion, type 2 cytokine production and eosinophilia was drastically reduced in the absence of macrophage A20 expression, while neutrophils and interstitial macrophages in lung were increased. In vitro, IL-33-mediated NF-κB activation was only weakly affected in A20-deficient macrophages. However, in the absence of A20, IL-33 gained the ability to activate STAT1 signalling and STAT1-dependent gene expression. Surprisingly, A20-deficient macrophages produced IFN-γ in response to IL-33, which was fully STAT1-dependent. Furthermore, STAT1 deficiency partially restored the ability of IL-33 to induce ILC2 expansion and eosinophilia in myeloid cell-specific A20 knockout mice.
Conclusion: We reveal a novel role for A20 as a negative regulator of IL-33-induced STAT1 signalling and IFN-γ production in macrophages, which determines lung immune responses.
Clinical implications: Our findings may eventually help to identify strategies that allow a better stratification of patients, leading to enhanced treatment efficacy.
背景：IL-33在哮喘和特应性皮炎等过敏性疾病的发病机制中起着重要作用。从肺上皮细胞释放后，IL-33主要驱动2型免疫反应，伴有嗜酸性粒细胞增多和IL-4、IL-5和IL-13的大量产生。然而，几项研究表明，IL-33也可以驱动1型免疫反应。
目的：关于IL-33是否诱导1型或2型免疫反应的机制仍存在重要问题。在这里，我们重点关注A20在巨噬细胞中IL-33信号传导的调节和IL-33诱导的肺免疫中的作用。
方法：我们研究了IL-33处理的小鼠肺部的免疫反应，这些小鼠的骨髓细胞中特异性缺乏A20。我们还分析了A20缺陷骨髓来源的巨噬细胞中的IL-33信号传导。
结果：在巨噬细胞A20不表达的情况下，IL-33诱导的肺ILC2扩张、2型细胞因子产生和嗜酸性粒细胞增多显著减少，而肺中的中性粒细胞和间质巨噬细胞增加。在体外，IL-33介导的NF-κB活化仅在A20缺陷巨噬细胞中受到微弱影响。然而，在缺乏A20的情况下，IL-33获得了激活STAT1信号传导和STAT1依赖性基因表达的能力。令人惊讶的是，A20缺陷的巨噬细胞对IL-33产生IFN-γ，IL-33完全依赖于STAT1。此外，STAT1缺乏部分恢复了IL-33在髓细胞特异性A20敲除小鼠中诱导ILC2扩增和嗜酸性粒细胞增多的能力。
结论：我们揭示了A20作为IL-33诱导的巨噬细胞STAT1信号传导和IFN-γ产生的负调节因子的新作用，IFN-γ的产生决定了肺免疫反应。
临床意义：我们的研究结果可能最终有助于确定更好地对患者进行分层的策略，从而提高治疗效果。
(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. 2023 Mar 8;S0091-6749(23)00287-7. doi: 10.1016/j.jaci.2023.02.026.)
(J Allergy Clin Immunol. 2023 Mar 8;S0091-6749(23)00287-7. doi: 10.1016/j.jaci.2023.02.026.)
A20 is a master switch of IL-33 signalling in macrophages and determines IL-33-induced lung immunity
Aurora Holgado, Zhuangzhuang Liu, Aigerim Aidarova, Christina Mueller, Mira Haegman, Yasmine Driege, Marja Kreike, Charlotte L Scott, Inna S Afonina, Rudi Beyaert
Abstract
Background: IL-33 plays a major role in the pathogenesis of allergic diseases such as asthma and atopic dermatitis. Upon its release from lung epithelial cells, IL-33 primarily drives type 2 immune responses, accompanied by eosinophilia and robust production of IL-4, IL-5 and IL-13. However, several studies show that IL-33 can also drive a type 1 immune response.
Objective: Important questions remain regarding the mechanisms that determine whether IL-33 induces a type 1 or type 2 immune response. Here we focus on the role of A20 in the regulation of IL-33 signalling in macrophages and IL-33-induced lung immunity.
Methods: We studied the immunological response in lungs of IL-33-treated mice that specifically lack A20 in myeloid cells. We also analysed IL-33 signalling in A20-deficient bone marrow derived macrophages.
Results: IL-33-induced lung ILC2 expansion, type 2 cytokine production and eosinophilia was drastically reduced in the absence of macrophage A20 expression, while neutrophils and interstitial macrophages in lung were increased. In vitro, IL-33-mediated NF-κB activation was only weakly affected in A20-deficient macrophages. However, in the absence of A20, IL-33 gained the ability to activate STAT1 signalling and STAT1-dependent gene expression. Surprisingly, A20-deficient macrophages produced IFN-γ in response to IL-33, which was fully STAT1-dependent. Furthermore, STAT1 deficiency partially restored the ability of IL-33 to induce ILC2 expansion and eosinophilia in myeloid cell-specific A20 knockout mice.
Conclusion: We reveal a novel role for A20 as a negative regulator of IL-33-induced STAT1 signalling and IFN-γ production in macrophages, which determines lung immune responses.
Clinical implications: Our findings may eventually help to identify strategies that allow a better stratification of patients, leading to enhanced treatment efficacy.
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