Induction of the antiviral factors APOBEC3A and RSAD2 upon CCL2 neutralization in primary human macrophages involves NF-κB, JAK/STAT, and gp130 signaling.

IF 3.6 3区 医学 Q3 CELL BIOLOGY Journal of Leukocyte Biology Pub Date : 2024-10-01 DOI:10.1093/jleuko/qiae123
Daniela Angela Covino, Iole Farina, Laura Catapano, Silvia Sozzi, Francesca Spadaro, Serena Cecchetti, Cristina Purificato, Maria Cristina Gauzzi, Laura Fantuzzi
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Abstract

The CCL2/CC chemokine receptor 2 axis plays key roles in the pathogenesis of HIV-1 infection. We previously reported that exposure of monocyte-derived macrophages to CCL2 neutralizing antibody (αCCL2 Ab) restricted HIV-1 replication at postentry steps of the viral life cycle. This effect was associated with induction of transcripts coding for innate antiviral proteins, including APOBEC3A and RSAD2. This study aimed at identifying the signaling pathways involved in induction of these factors by CCL2 blocking in monocyte-derived macrophages. Through a combination of pharmacologic inhibition, quantitative reverse transcription polymerase chain reaction, Western blotting, and confocal laser-scanning microscopy, we demonstrated that CCL2 neutralization activates the canonical NF-κB and JAK/STAT pathways, as assessed by time-dependent phosphorylation of IκB, STAT1, and STAT3 and p65 nuclear translocation. Furthermore, pharmacologic inhibition of IκB kinase and JAKs strongly reduced APOBEC3A and RSAD2 transcript accumulation elicited by αCCL2 Ab treatment. Interestingly, exposure of monocyte-derived macrophages to αCCL2 Ab resulted in induction of IL-6 family cytokines, and interference with glycoprotein 130, the common signal-transducing receptor subunit shared by these cytokines, inhibited APOBEC3A and RSAD2 upregulation triggered by CCL2 neutralization. These results provide novel insights into the signal transduction pathways underlying the activation of innate responses triggered by CCL2 neutralization in macrophages. Since this response was found to be associated with protective antiviral effects, the new findings may help design innovative therapeutic approaches targeting CCL2 to strengthen host innate immunity.

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原代人类巨噬细胞中的 CCL2 中和后,抗病毒因子 APOBEC3A 和 RSAD2 的诱导涉及 NF-kB、JAK/STAT 和 gp130 信号传导。
CC趋化因子配体2(CCL2)/CC趋化因子受体2轴在人类免疫缺陷病毒1型(HIV-1)感染的发病机制中起着关键作用。我们以前曾报道过,单核细胞衍生巨噬细胞(MDM)暴露于 CCL2 中和抗体(αCCL2 Ab)会在病毒生命周期的后进入步骤中限制 HIV-1 的复制。这种效应与先天性抗病毒蛋白编码转录本的诱导有关,其中包括载脂蛋白 B mRNA 编辑酶催化多肽样 3A(APOBEC3A)和含 S-腺苷蛋氨酸自由基结构域 2(RSAD2)。本研究旨在确定CCL2阻断MDMs诱导这些因子的信号通路。通过药理抑制、定量 RT-PCR、Western 印迹和激光扫描共聚焦显微镜等综合方法,我们证明了 CCL2 中和可激活典型的 NF-kB 和 JAK/STAT 通路,这可通过 IkB、STAT1 和 STAT3 的时间依赖性磷酸化和 p65 核转位来评估。此外,对 I kappa B 激酶和 JAKs 的药理抑制可大大减少 αCCL2 Ab 处理引起的 APOBEC3A 和 RSAD2 转录物积累。有趣的是,MDMs 暴露于 αCCL2 Ab 会导致 IL-6 家族细胞因子的诱导,而干扰糖蛋白 130(这些细胞因子共有的信号转导受体亚基)会抑制 CCL2 中和引发的 APOBEC3A 和 RSAD2 的上调。这些结果为了解巨噬细胞中 CCL2 中和引发的先天性反应激活的信号转导途径提供了新的视角。由于发现这种反应与保护性抗病毒作用有关,这些新发现可能有助于设计针对 CCL2 的创新治疗方法,以增强宿主的先天免疫力。
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来源期刊
Journal of Leukocyte Biology
Journal of Leukocyte Biology 医学-免疫学
CiteScore
11.50
自引率
0.00%
发文量
358
审稿时长
2 months
期刊介绍: JLB is a peer-reviewed, academic journal published by the Society for Leukocyte Biology for its members and the community of immunobiologists. The journal publishes papers devoted to the exploration of the cellular and molecular biology of granulocytes, mononuclear phagocytes, lymphocytes, NK cells, and other cells involved in host physiology and defense/resistance against disease. Since all cells in the body can directly or indirectly contribute to the maintenance of the integrity of the organism and restoration of homeostasis through repair, JLB also considers articles involving epithelial, endothelial, fibroblastic, neural, and other somatic cell types participating in host defense. Studies covering pathophysiology, cell development, differentiation and trafficking; fundamental, translational and clinical immunology, inflammation, extracellular mediators and effector molecules; receptors, signal transduction and genes are considered relevant. Research articles and reviews that provide a novel understanding in any of these fields are given priority as well as technical advances related to leukocyte research methods.
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