tetano
Editor, Senior Moderator
Commun Biol
. 2024 Oct 14;7(1):1321.
doi: 10.1038/s42003-024-07025-4. FPR1 signaling aberrantly regulates S100A8/A9 production by CD14[SUP]+[/SUP]FCN1[SUP]hi[/SUP] macrophages and aggravates pulmonary pathology in severe COVID-19
Zhongyi Wang[SUP] #[/SUP][SUP] 1 [/SUP], Yi Wang[SUP] #[/SUP][SUP] 1 [/SUP], Qing Yan[SUP] #[/SUP][SUP] 1 [/SUP], Changlin Cai[SUP] 1 [/SUP], Ying Feng[SUP] 1 [/SUP], Qinghan Huang[SUP] 1 [/SUP], Ting Li[SUP] 1 [/SUP], Shenzhen Yuan[SUP] 1 [/SUP], Juan Huang[SUP] 2 [/SUP], Zhi-Hui Luo[SUP] 3 [/SUP], Jingjiao Zhou[SUP] 4 [/SUP]
Affiliations
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 CD14[SUP]+[/SUP]FCN1[SUP]hi[/SUP] 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 CD14[SUP]+[/SUP]FCN1[SUP]hi[/SUP] macrophages presented the highest scores of alarmin S100, and possibly served as the trigger and amplifier of inflammation in severe COVID-19. These CD14[SUP]+[/SUP]FCN1[SUP]hi[/SUP] 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.
. 2024 Oct 14;7(1):1321.
doi: 10.1038/s42003-024-07025-4. FPR1 signaling aberrantly regulates S100A8/A9 production by CD14[SUP]+[/SUP]FCN1[SUP]hi[/SUP] macrophages and aggravates pulmonary pathology in severe COVID-19
Zhongyi Wang[SUP] #[/SUP][SUP] 1 [/SUP], Yi Wang[SUP] #[/SUP][SUP] 1 [/SUP], Qing Yan[SUP] #[/SUP][SUP] 1 [/SUP], Changlin Cai[SUP] 1 [/SUP], Ying Feng[SUP] 1 [/SUP], Qinghan Huang[SUP] 1 [/SUP], Ting Li[SUP] 1 [/SUP], Shenzhen Yuan[SUP] 1 [/SUP], Juan Huang[SUP] 2 [/SUP], Zhi-Hui Luo[SUP] 3 [/SUP], Jingjiao Zhou[SUP] 4 [/SUP]
Affiliations
- PMID: 39402337
- PMCID: PMC11473795
- DOI: 10.1038/s42003-024-07025-4
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 CD14[SUP]+[/SUP]FCN1[SUP]hi[/SUP] 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 CD14[SUP]+[/SUP]FCN1[SUP]hi[/SUP] macrophages presented the highest scores of alarmin S100, and possibly served as the trigger and amplifier of inflammation in severe COVID-19. These CD14[SUP]+[/SUP]FCN1[SUP]hi[/SUP] 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.