CCL7 Is a Negative Regulator of Cutaneous Inflammation Following Leishmania major Infection
CCL7 Is a Negative Regulator of Cutaneous Inflammation Following Leishmania major Infection
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DOI：
10.3389/fimmu.2018.03063
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发表时间：
2019-01-08
影响因子：
7.3
通讯作者：
Fowell, Deborah J.
中科院分区：
文献类型：
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作者：
Ford, Jill;Hughson, Angela;Fowell, Deborah J.
已知趋化因子CCL7（MCP 3）促进许多先天性免疫细胞类型的募集，包括单核细胞和嗜中性粒细胞至细菌和病毒感染部位以及嗜酸性粒细胞和嗜碱性粒细胞至过敏性炎症部位。CCL7上调与许多炎症环境相关，包括感染、心血管疾病和肿瘤微环境。CCL7的多效性作用部分是由于其能够结合多种趋化因子受体，即CCR 1、CCR 2、CCR 3、CCR 5和CCR 10。CCL7阻断或CCL7缺乏通常以炎症减少和病原体控制不良为标志。在大型利什曼原虫感染的情况下，感染后1 - 2周，CCL7在皮肤中特异性上调，但其在利什曼原虫中的作用是特异性的。主要控制不明确。确定CCL7对L.我们主要感染WT和CCL7（-/-）C57BL/6小鼠。L. CCL7缺陷小鼠的主要感染导致感染后2周感染皮肤中炎症的意外增加。观察到免疫细胞亚群的广泛增加，但以增强的嗜中性粒细胞浸润为主。中性粒细胞募集增加与感染皮肤中IL-17基因谱增强相关。CCL7在体外显示直接拮抗中性粒细胞迁移，并且CCL7在体内添加特异性地减少中性粒细胞流入感染的皮肤，揭示了CCL7在限制L.严重感染在CCL7缺陷小鼠中增强的嗜中性粒细胞浸润改变了L.主要感染的宿主细胞，感染的中性粒细胞相对于单核细胞/巨噬细胞的比率增加。目的探讨CCL7缺陷对L.主要对照我们分析了感染部位和引流LN和脾脏中内脏的寄生虫负荷。CCL7（-/-）小鼠支持与其WT C57BL/6对应物类似的稳健的皮肤寄生虫控制。相比之下，CCL7缺乏导致更大的寄生虫传播和脾脏中的寄生虫控制不良。我们的研究揭示了CCL 7在L早期负调节皮肤炎症（特别是中性粒细胞）中的新作用。严重感染我们认为，CCL7介导的抑制皮肤中的早期免疫反应可能会限制寄生虫传播的能力，而不影响皮肤控制。
The chemokine CCL7 (MCP3) is known to promote the recruitment of many innate immune cell types including monocytes and neutrophils to sites of bacterial and viral infection and eosinophils and basophils to sites of allergic inflammation. CCL7 upregulation has been associated with many inflammatory settings including infection, cardiovascular disease, and the tumor microenvironment. CCL7's pleotropic effects are due in part to its ability to bind numerous chemokine receptors, namely CCR1, CCR2, CCR3, CCR5, and CCR10. CCL7-blockade or CCL7-deficiency is often marked by decreased inflammation and poor pathogen control. In the context of Leishmania major infection, CCL7 is specifically upregulated in the skin one-2 weeks after infection but its role in L. major control is unclear. To determine CCL7's impact on the response to L. major we infected WT and CCL7(-/-) C57BL/6 mice. L. major infection of CCL7-deficient mice led to an unexpected increase in inflammation in the infected skin 2 weeks post-infection. A broad increase in immune cell subsets was observed but was dominated by enhanced neutrophilic infiltration. Increased neutrophil recruitment was associated with an enhanced IL-17 gene profile in the infected skin. CCL7 was shown to directly antagonize neutrophil migration in vitro and CCL7 add-back in vivo specifically reduced neutrophil influx into the infected skin revealing an unexpected role for CCL7 in limiting neutrophil recruitment during L. major infection. Enhanced neutrophilic infiltration in CCL7-deficient mice changed the balance of L. major infected host cells with an increase in the ratio of infected neutrophils over monocytes/macrophages. To determine the consequence of CCL7 deficiency on L. major control we analyzed parasite load cutaneously at the site of infection and viscerally in the draining LN and spleen. The CCL7(-/-) mice supported robust cutaneous parasite control similar to their WT C57BL/6 counterparts. In contrast, CCL7-deficiency led to greater parasite dissemination and poor parasite control in the spleen. Our studies reveal a novel role for CCL7 in negatively regulating cutaneous inflammation, specifically neutrophils, early during L. major infection. We propose that CCL7-mediated dampening of the early immune response in the skin may limit the ability of the parasite to disseminate without compromising cutaneous control.