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FPR1 信号异常调控 CD14+FCN1 巨噬细胞 S100A8/A9 的产生，加重重症 COVID-19 的肺部病变。

FPR1 signaling aberrantly regulates S100A8/A9 production by CD14FCN1 macrophages and aggravates pulmonary pathology in severe COVID-19.

机构信息

Department of Biology and Genetics, The College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan, China.

Department of Hematology, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

出版信息

Commun Biol. 2024 Oct 14;7(1):1321. doi: 10.1038/s42003-024-07025-4.

DOI:10.1038/s42003-024-07025-4
PMID:39402337
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11473795/
Abstract

Excessive alarmins S100A8/A9 escalate the inflammation and even exacerbate immune-driven thrombosis and multi-organ damage. However, the regulatory mechanisms of S100A8/A9 expression in infectious diseases remain unclear. In this study, high-dimensional transcriptomic data analyses revealed a high proportion of CD14FCN1 macrophages within the pulmonary niche post-severe SARS-CoV-2 infection. By constructing the S100-coexpression gene list and supervised module scoring, we found that CD14FCN1 macrophages presented the highest scores of alarmin S100, and possibly served as the trigger and amplifier of inflammation in severe COVID-19. These CD14FCN1 cells lacked the positive regulatory activity of transcription factor PPARγ, and lost their differentiation ability towards mature macrophages. Ex vivo experiments further validated that the epithelial cells with high ORF-3a expression promoted the expression and secretion of S100A8/A9 through ANXA1/SAA1-FPR1 signaling. S100A8/A9 heterodimers, as well as the co-localization of S100A8/A9 with microtubules, were both diminished by the FPR1 inhibitor. Phospho-kinase protein array indicated that STAT3 promoted transcription, and PLC-γ and ERK1/2 pathways were involved in the hetero-dimerization and unconventional secretion of S100A8/A9. Our study highlights the pivotal role of FPR1 signaling in the excessive production of S100A8/A9 and provides a promising target for the prevention and control of severe COVID-19 and post-acute COVID-19 sequelae.

摘要

过度的警报素 S100A8/A9 会加剧炎症，甚至恶化免疫驱动的血栓形成和多器官损伤。然而，S100A8/A9 在感染性疾病中的表达调控机制尚不清楚。在这项研究中，通过高维转录组数据分析，我们发现严重 SARS-CoV-2 感染后肺部龛内存在高比例的 CD14FCN1 巨噬细胞。通过构建 S100 共表达基因列表和监督模块评分，我们发现 CD14FCN1 巨噬细胞呈现出最高的警报素 S100 评分，可能是严重 COVID-19 中炎症的触发和放大因素。这些 CD14FCN1 细胞缺乏转录因子 PPARγ 的正向调控活性，并且丧失了向成熟巨噬细胞分化的能力。体外实验进一步验证了高表达 ORF-3a 的上皮细胞通过 ANXA1/SAA1-FPR1 信号促进 S100A8/A9 的表达和分泌。S100A8/A9 异二聚体以及 S100A8/A9 与微管的共定位都被 FPR1 抑制剂所减少。磷酸化激酶蛋白阵列表明 STAT3 促进转录，PLC-γ 和 ERK1/2 通路参与 S100A8/A9 的异二聚化和非经典分泌。我们的研究强调了 FPR1 信号在 S100A8/A9 过度产生中的关键作用，并为严重 COVID-19 和急性 COVID-19 后后遗症的预防和控制提供了一个有前景的靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9248/11473795/998b37cccf1d/42003_2024_7025_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9248/11473795/6cf2727069f0/42003_2024_7025_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9248/11473795/2cf59f27f9a4/42003_2024_7025_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9248/11473795/29372f8e9506/42003_2024_7025_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9248/11473795/2a1c4e9878a2/42003_2024_7025_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9248/11473795/aa926737eee6/42003_2024_7025_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9248/11473795/42685168706f/42003_2024_7025_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9248/11473795/998b37cccf1d/42003_2024_7025_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9248/11473795/6cf2727069f0/42003_2024_7025_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9248/11473795/2cf59f27f9a4/42003_2024_7025_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9248/11473795/29372f8e9506/42003_2024_7025_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9248/11473795/2a1c4e9878a2/42003_2024_7025_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9248/11473795/aa926737eee6/42003_2024_7025_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9248/11473795/42685168706f/42003_2024_7025_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9248/11473795/998b37cccf1d/42003_2024_7025_Fig7_HTML.jpg

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