巨噬细胞的持续 IL-4 引发增强了对 TLR7/8 配体 R848 的炎症反应,Journal of Leukocyte Biology

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巨噬细胞的持续 IL-4 引发增强了对 TLR7/8 配体 R848 的炎症反应
Journal of Leukocyte Biology ( IF 3.6 ) Pub Date : 2021-05-19 , DOI: 10.1002/jlb.3a0520-293rr
Andra Banete ₁ , Katrina Gee ₁ , Sameh Basta ₁

Affiliation

巨噬细胞 (Mφ) 具有高度可塑性，并且可以根据其局部环境中不同刺激的存在而获得多种功能表型。由白细胞介素 (IL)-4 刺激的 Mφ 可诱导另一种激活状态并作为抗炎细胞发挥作用并促进组织修复。然而，有压倒性的证据表明 IL-4 可以在促进炎症中发挥作用。在哮喘和过敏性炎症中，IL-4 介导导致组织损伤的促炎反应。因此，IL-4 对免疫反应结果的影响受到微环境中存在的其他辅助因子和细胞因子的极大影响。TLR7/8 激动剂 R848 (resiquimod) 是一种新型疫苗佐剂，可引发强烈的 Th1 偏态反应，但其作为疫苗佐剂的功效显示出不同的结果。目前尚不清楚 IL-4 的存在是否会抑制或增强对 TLR7 激动剂的免疫反应。在本研究中，我们试图研究 IL-4 诱导的 Mφ 极化对 R848 刺激结果的影响。在鼠脾衍生的 Mφ 中测量了激活标志物的表达和细胞因子的产生。在激活的 Mφ 中评估了先天识别分子和相关转录因子的蛋白质表达水平，包括视黄酸诱导基因 I、线粒体抗病毒信号蛋白、干扰素基因刺激物 (STING) 和 IFN 调节因子。这些在控制病毒复制和最佳 CD8+ T 细胞启动中起着至关重要的作用。我们报告说，单独使用 IL-4 的持续启动促进了 Mφ 的抗病毒反应，并增强对 R848 治疗的促炎反应。这凸显了需要更好地了解 IL-4 促炎功能及其作为广效抗病毒药物与 R848 联合使用的潜在用途，可与其他疗法联合使用，以针对新出现的感染的先天免疫臂。

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Sustained IL-4 priming of macrophages enhances the inflammatory response to TLR7/8 ligand R848

Macrophages (Mϕ) are highly plastic, and can acquire a variety of functional phenotypes depending on the presence of different stimuli in their local environment. Mφ stimulated by interleukin (IL)-4 induce an alternative activation state and function as anti-inflammatory cells and promote tissue repair. However, there is overwhelming evidence that IL-4 can play a role in promoting inflammation. In asthma and allergic inflammation, IL-4 mediates proinflammatory responses that lead to tissue damage. Thus the effect of IL-4 on the outcome of the immune responses is greatly influenced by other cofactors and cytokines present in the microenvironment. R848 (resiquimod), a TLR7/8 agonist is a novel vaccine adjuvant, triggering a strong Th1-skewed response but its efficacy as a vaccine adjuvant shows variable results. It is not currently known whether the presence of IL-4 can dampen or enhance immunity in response to TLR7 agonists. In the present study, we sought to investigate the impact of IL-4-induced Mφ polarization on the outcome of R848 stimulation. The activation marker expression and production of cytokines were measured in murine spleen-derived Mφ. Protein expression levels of innate recognition molecules and transcription factors involved, including retinoic-acid inducible gene I, mitochondrial antiviral signaling protein, stimulator of interferon genes (STING), and IFN regulatory factors were evaluated in activated Mφ. These play a crucial role in the control of viral replication and optimal CD8+ T cell priming. We report that sustained priming with IL-4 alone promotes an antiviral response in Mφ, and enhances proinflammatory responses to R848 treatment. This highlights the need for better understanding of IL-4 proinflammatory functions and its potential use as a broad-acting antiviral in combination with R848 may be used in combination with other therapies to target the innate arm of immunity against emerging infections.

更新日期：2021-05-19

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