TRAF1 suppresses antifungal immunity through CXCL1-mediated neutrophil recruitment during Candida albicans intradermal infection
TRAF1 suppresses antifungal immunity through CXCL1-mediated neutrophil recruitment during Candida albicans intradermal infection
复制标题
TRAF1 在白色念珠菌皮内感染期间通过 CXCL1 介导的中性粒细胞募集抑制抗真菌免疫
DOI：
10.1186/s12964-020-00532-x
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发表时间：
2020-02-24
影响因子：
8.4
通讯作者：
Wu, Zhiyuan
中科院分区：
文献类型：
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作者：
Bai, Wenjuan;Wang, Qingqing;Wu, Zhiyuan
背景白色念珠菌是人类最常见的条件致病真菌。趋化因子配体CXCL 1通过募集中性粒细胞在真菌感染中起保护作用。TRAF 1（肿瘤坏死因子相关因子1）可以高度诱导的促炎刺激，如LPS和TNF，并已牵连在感染性休克。然而，TRAF 1在感染，特别是真菌感染中的作用仍然难以捉摸。在此，我们揭示了TRAF 1通过调节CXCL 1诱导和中性粒细胞募集来抑制对皮肤内白念珠菌感染的抗真菌免疫应答。建立了白色念珠菌皮内感染。产生Traf 1 −/−小鼠和Traf 1 −/−永生化的人角质形成细胞。使用p65抑制剂雷公藤内酯醇、STAT 1抑制剂氟达拉滨、嗜中性粒细胞耗竭抗体Ly 6 G和CXCL 1中和抗体。通过实时荧光定量PCR和ELISA评估促炎细胞因子和趋化因子的表达，并通过Western印迹分析信号分子的活化。苏木精和伊红染色和高碘酸希夫染色分别用于组织学或真菌检测。免疫荧光和流式细胞术分析用于评估免疫细胞浸润。结果TRAF 1基因敲除小鼠对白色念珠菌皮肤感染的抑制作用明显增强，中性粒细胞聚集增加，真菌负荷降低。趋化因子CXCL 1在TRAF 1缺陷的巨噬细胞中被热灭活C上调。白色念珠菌机制上，TRAF 1缺陷型巨噬细胞显示转录因子NFκB p65的活化增加。在TNF刺激后，通过降低转录因子STAT 1的活化，人CXCL 8在TRAF 1缺陷型人角质形成细胞中也被高度诱导。TRAF 1缺陷型巨噬细胞在含C.结论TRAF 1基因敲除小鼠能更好地控制皮肤真菌感染，这一过程可归因于CXCL-中性粒细胞轴。TRAF 1可能分别通过转录因子NFκB和STAT 1调节巨噬细胞和角质形成细胞中CXCL 1的表达。我们的发现为理解宿主防御C的免疫调节机制提供了新的见解。白色念珠菌感染。图示摘要
BackgroundCandida albicansis the most common opportunistic human fungal pathogen. The chemokine ligand CXCL1 plays a protective role in fungal infection through the recruitment of neutrophils. TRAF1 (tumor necrosis factor-associated factor 1) can be highly induced by proinflammatory stimuli such as LPS and TNF and has been implicated in septic shock. However, the role of TRAF1 in infection, especially fungal infection, remains elusive. Herein, we reveal that TRAF1 suppresses the antifungal immune response toCandida albicansintradermal infection through the regulation of CXCL1 induction and neutrophil recruitment.MethodsA mouse model ofC. albicansintradermal infection was established. TheTraf1−/−mice andTraf1−/−immortalized human keratinocytes were generated. The p65 inhibitor triptolide, STAT1 inhibitor fludarabine, neutrophil-depletion antibody Ly6G, and neutralizing antibody for CXCL1 were utilized. The expression of proinflammatory cytokines and chemokines was assessed by real-time PCR and ELISA, and the activation of signaling molecules was analyzed by Western blotting. Hematoxylin and eosin staining and periodic acid Schiff staining were used for histology or fungal detection, respectively. The immunofluorescence and flow cytometry analyses were employed in the assessment of immune cell infiltration. Bone marrow transplantation and adoptive transfer experiments were conducted to establish a role for TRAF1 in the macrophage compartment in fungal skin infection.ResultsTRAF1-deficient mice demonstrated improved control ofCandida albicansintradermal infection, and concomitant increase in neutrophil recruitment and reduction in fungal burden. The chemokine CXCL1 was upregulated in the TRAF1-deficient macrophages treated with heat-killedC. albicans. Mechanistically, TRAF1-deficient macrophages showed increased activation of transcription factor NFκB p65. The human CXCL8 was also highly induced in the TRAF1-deficient human keratinocytes upon TNF stimulation through decreasing the activation of transcription factor STAT1. TRAF1-deficient macrophages played a critical role in containing theC. albicansskin infection in vivo.ConclusionTRAF1-deficient mice can better control fungal infection in the skin, a process attributable to the CXCL-neutrophil axis. Mechanistically, TRAF1 likely regulates CXCL1 expression in both macrophages and keratinocytes through the transcriptional factor NFκB and STAT1, respectively. Our finding offers new insight into the understanding of the immune regulatory mechanisms in host defense againstC. albicansinfection.Graphical abstract