Unit of Molecular Signal Transduction in Inflammation, VIB-UGent Center for Inflammation Research, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Ghent, Belgium.
J Allergy Clin Immunol. 2023 Jul;152(1):244-256.e4. doi: 10.1016/j.jaci.2023.02.026. Epub 2023 Mar 9.
IL-33 plays a major role in the pathogenesis of allergic diseases such as asthma and atopic dermatitis. On 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.
We sought to determine the role of A20 in the regulation of IL-33 signaling in macrophages and IL-33-induced lung immunity.
We studied the immunologic response in lungs of IL-33-treated mice that specifically lack A20 in myeloid cells. We also analyzed IL-33 signaling in A20-deficient bone marrow-derived macrophages.
IL-33-induced lung innate lymphoid cell type 2 expansion, type 2 cytokine production, and eosinophilia were drastically reduced in the absence of macrophage A20 expression, whereas neutrophils and interstitial macrophages in lungs were increased. In vitro, IL-33-mediated nuclear factor kappa B activation was only weakly affected in A20-deficient macrophages. However, in the absence of A20, IL-33 gained the ability to activate signal transducer and activator of transcription 1 (STAT1) signaling 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.
We reveal a novel role for A20 as a negative regulator of IL-33-induced STAT1 signaling and IFN-γ production in macrophages, which determines lung immune responses.
IL-33 在哮喘和特应性皮炎等过敏性疾病的发病机制中起主要作用。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，一些研究表明，IL-33 也可以驱动 1 型免疫反应。
我们旨在确定 A20 在调节巨噬细胞中 IL-33 信号转导和 IL-33 诱导的肺免疫中的作用。
我们研究了在骨髓来源的巨噬细胞中特异性缺乏 A20 的 IL-33 处理小鼠的免疫反应。我们还分析了 A20 缺陷型骨髓来源巨噬细胞中的 IL-33 信号转导。
在缺乏巨噬细胞 A20 表达的情况下，IL-33 诱导的肺固有淋巴细胞 2 型扩增、2 型细胞因子产生和嗜酸性粒细胞增多明显减少，而肺部的中性粒细胞和间质性巨噬细胞增加。在体外，A20 缺陷型巨噬细胞中，IL-33 介导的核因子 kappa B 激活仅受到轻微影响。然而，在缺乏 A20 的情况下，IL-33 获得了激活信号转导和转录激活因子 1（STAT1）信号转导和 STAT1 依赖性基因表达的能力。令人惊讶的是，A20 缺陷型巨噬细胞在受到 IL-33 刺激时会产生 IFN-γ，这完全依赖于 STAT1。此外，STAT1 缺陷部分恢复了 IL-33 在骨髓细胞特异性 A20 敲除小鼠中诱导 ILC2 扩增和嗜酸性粒细胞增多的能力。
我们揭示了 A20 作为 IL-33 诱导的 STAT1 信号转导和巨噬细胞 IFN-γ产生的负调节剂的新作用，这决定了肺部免疫反应。
