摘要
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.
摘要译文
巨噬细胞（Mφ）是高度塑料的，并且可以根据当地环境中存在不同刺激的存在，获取各种功能表型。通过白细胞介素（IL）刺激的Mφ-4诱导替代活化状态并用作抗炎细胞并促进组织修复。然而，有压倒性的证据表明IL-4可以发挥促进炎症的作用。在哮喘和过敏性炎症中，IL-4介导促炎反应，导致组织损伤。因此，IL-4对免疫应答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影响。 R848（籽粒），TLR7 / 8激动剂是一种新型疫苗佐剂，触发强Th1偏斜的响应，但作为疫苗佐剂的功效显示出可变结果。目前尚不知道IL-4的存在是否可以抑制或增强响应TLR7激动剂的免疫。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中测量激活标记表达和细胞因子的产生。在活性的Mφ中评估了在活化的Mφ中评估了涉及的先天鉴别分子和转录因子的先天识别分子和转录因子的蛋白质表达水平，包括视黄酸诱导诱导基因I，受干扰素基因的刺激剂和IFN调节因子。这些在控制病毒复制和最佳CD8 + T细胞灌注中起着至关重要的作用。我们认为，单独的IL-4持续启动促进Mφ的抗病毒反应，并增强对R848治疗的促炎反应。这突出了更好地理解IL-4促炎功能的需求，并且其作为宽挥发的抗病毒与R848组合的潜在用途可以与其他疗法组合使用，以靶向免疫的先天动脉反对新兴感染。
Andra Banete[1];Katrina Gee[1];Sameh Basta[1]. Sustained IL-4 priming of macrophages enhances the inflammatory response to TLR7/8 ligand R848[J]. Journal of Leukocyte Biology, 2022,111(2): 401-413