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PU.1-CD23 信号通过驱动炎症反应介导肺部固有免疫抵抗烟曲霉感染。

PU.1-CD23 signaling mediates pulmonary innate immunity against Aspergillus fumigatus infection by driving inflammatory response.

机构信息

Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, and College of Clinical Medicine, Henan University of Science and Technology, No. 24, Jinghua Road, Jianxi District, Luoyang City, Henan Province, China.

Department of Respiratory Medicine, The Third Affiliated Hospital of Soochow University, Suzhou, China.

出版信息

BMC Immunol. 2023 Jan 17;24(1):4. doi: 10.1186/s12865-023-00539-2.

DOI:10.1186/s12865-023-00539-2
PMID:36650424
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9844028/
Abstract

BACKGROUND

Aspergillosis is a common cause of morbidity and mortality in immunocompromised populations. PU.1 is critical for innate immunity against Aspergillus fumigatus (AF) in macrophages. However, the molecular mechanism underlying PU.1 mediating immunity against AF infection in human alveolar macrophages (AMs) is still unclear.

METHODS

In this study, we detected the expressions of PU.1, CD23, p-ERK, CCL20 and IL-8 and key inflammatory markers IL-1β, IL-6, TNF-α and IL-12 in human THP-1-derived macrophages (HTMs) or PU.1/CD23-overexpressed immunodeficient mice with AF infection. Moreover, we examined these expressions in PU.1-overexpressed/interfered HTMs. Additionally, we detected the phagocytosis of macrophages against AF infection with altered PU.1 expression. Dual luciferase, ChIP and EMSAs were performed to detect the interaction of PU.1 and CD23. And we invested the histological changes in mouse lung tissues transfected with PU.1/CD23-expressing adenoviruses in AF infection.

RESULTS

The results showed that the expressions of PU.1, CD23, p-ERK, CCL20, IL-8, IL-1β, IL-6, TNF-α and IL-12 increased significantly with AF infection, and PU.1 regulated the later 8 gene expressions in HTMs. Moreover, CD23 was directly activated by PU.1, and overexpression of CD23 in PU.1-interfered HTMs upregulated IL-1β, IL-6, TNF-α and IL-12 levels which were downregulated by PU.1 interference. PU.1 overexpression strengthened the phagocytosis of the HTMs against AF. And injection of PU.1/CD23-expressing adenoviruses attenuated pathological defects in immunodeficient mouse lung tissues with AF infection. Adenovirus (Ad)-PU.1 increased the CD23, p-ERK, CCL20, IL-8 levels.

CONCLUSIONS

Our study concluded that PU.1-CD23 signaling mediates innate immunity against AF in lungs through regulating inflammatory response. Therefore, PU.1-CD23 may be a new anti-aspergillosis therapeutic for the treatment of invasive aspergillosis with the deepening of gene therapy and its wide application in the clinic.

摘要

背景

曲霉菌病是免疫功能低下人群发病和死亡的常见原因。PU.1 对巨噬细胞中针对烟曲霉（AF）的固有免疫至关重要。然而，PU.1 介导人肺泡巨噬细胞（AMs）对抗 AF 感染的免疫的分子机制尚不清楚。

方法

在这项研究中，我们检测了人类 THP-1 衍生巨噬细胞（HTMs）或过表达 PU.1/CD23 的免疫缺陷小鼠感染 AF 后 PU.1、CD23、p-ERK、CCL20 和 IL-8 以及关键炎症标志物 IL-1β、IL-6、TNF-α 和 IL-12 的表达。此外，我们还在过表达或干扰 PU.1 的 HTMs 中检测了这些表达。此外，我们检测了改变 PU.1 表达的巨噬细胞对 AF 感染的吞噬作用。进行了双荧光素酶、染色质免疫沉淀和电泳迁移率变动分析以检测 PU.1 和 CD23 的相互作用。并在 AF 感染中研究了转染了表达 PU.1/CD23 的腺病毒的小鼠肺组织的组织学变化。

结果

结果表明，AF 感染后 PU.1、CD23、p-ERK、CCL20、IL-8、IL-1β、IL-6、TNF-α 和 IL-12 的表达均显著增加，PU.1 调节了 HTMs 中的后 8 个基因的表达。此外，CD23 直接被 PU.1 激活，在被 PU.1 干扰的 HTMs 中过表达 CD23 可上调被 PU.1 干扰下调的 IL-1β、IL-6、TNF-α 和 IL-12 水平。PU.1 过表达增强了 HTMs 对 AF 的吞噬作用。并且，注射表达 PU.1/CD23 的腺病毒可减轻 AF 感染免疫缺陷小鼠肺组织的病理缺陷。腺病毒（Ad）-PU.1 增加了 CD23、p-ERK、CCL20、IL-8 的水平。

结论

我们的研究得出结论，PU.1-CD23 信号通过调节炎症反应介导肺部对 AF 的固有免疫。因此，PU.1-CD23 可能成为一种新的抗曲霉菌治疗方法，可用于治疗侵袭性曲霉菌病，随着基因治疗的深入研究及其在临床上的广泛应用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd73/9844028/d653cf68dfc3/12865_2023_539_Fig7_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd73/9844028/d653cf68dfc3/12865_2023_539_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd73/9844028/ec4f07b5cba3/12865_2023_539_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd73/9844028/676be8f6d2b7/12865_2023_539_Fig2_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd73/9844028/8efefb9a2d98/12865_2023_539_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd73/9844028/3523f5e2a630/12865_2023_539_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd73/9844028/d653cf68dfc3/12865_2023_539_Fig7_HTML.jpg

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