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

Communications Biology, ISSN: 2399-3642, Vol: 7, Issue: 1, Page: 1321
2024
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Article Description

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.

Bibliographic Details

Wang, Zhongyi; Wang, Yi; Yan, Qing; Cai, Changlin; Feng, Ying; Huang, Qinghan; Li, Ting; Yuan, Shenzhen; Huang, Juan; Luo, Zhi-Hui; Zhou, Jingjiao

Springer Science and Business Media LLC

Medicine; Biochemistry, Genetics and Molecular Biology; Agricultural and Biological Sciences

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