CREB1-driven CXCR4hi neutrophils promote skin inflammation in mouse models and human patients

Jiaoling Chen, Yaxing Bai, Ke Xue, Zhiguo Li, Zhenlai Zhu, Qingyang Li, Chen Yu, Bing Li, Shengxian Shen, Pei Qiao, Caixia Li, Yixin Luo, Hongjiang Qiao, Erle Dang, Wen Yin, Johann E. Gudjonsson (), Gang Wang () and Shuai Shao ()
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Jiaoling Chen: Fourth Military Medical University
Yaxing Bai: Fourth Military Medical University
Ke Xue: Fourth Military Medical University
Zhiguo Li: Fourth Military Medical University
Zhenlai Zhu: Fourth Military Medical University
Qingyang Li: Fourth Military Medical University
Chen Yu: Fourth Military Medical University
Bing Li: Fourth Military Medical University
Shengxian Shen: Fourth Military Medical University
Pei Qiao: Fourth Military Medical University
Caixia Li: Fourth Military Medical University
Yixin Luo: Fourth Military Medical University
Hongjiang Qiao: Fourth Military Medical University
Erle Dang: Fourth Military Medical University
Wen Yin: Fourth Military Medical University
Johann E. Gudjonsson: University of Michigan
Gang Wang: Fourth Military Medical University
Shuai Shao: Fourth Military Medical University

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract Neutrophils have a pathogenic function in inflammation via releasing pro-inflammatory mediators or neutrophil extracellular traps (NETs). However, their heterogeneity and pro-inflammatory mechanisms remain unclear. Here, we demonstrate that CXCR4hi neutrophils accumulate in the blood and inflamed skin in human psoriasis, and correlate with disease severity. Compared to CXCR4lo neutrophils, CXCR4hi neutrophils have enhanced NETs formation, phagocytic function, neutrophil degranulation, and overexpression of pro-inflammatory cytokines and chemokines in vitro. This is accompanied by a metabolic shift in CXCR4hi neutrophils toward glycolysis and lactate release, thereby promoting vascular permeability and remodeling. CXCR4 expression in neutrophils is dependent on CREB1, a transcription factor activated by TNF and CXCL12, and regulated by de novo synthesis. In vivo, CXCR4hi neutrophil infiltration amplifies skin inflammation, whereas blockade of CXCR4hi neutrophils through CXCR4 or CXCL12 inhibition leads to suppression of immune responses. In this work, our study identifies CREB1 as a critical regulator of CXCR4hi neutrophil development and characterizes the contribution of CXCR4hi neutrophils to vascular remodeling and inflammatory responses in skin.

Date: 2023
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DOI: 10.1038/s41467-023-41484-3

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