2. Academic Validation
  3. CREB1-driven CXCR4hi neutrophils promote skin inflammation in mouse models and human patients

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

  • Nat Commun. 2023 Sep 22;14(1):5894. doi: 10.1038/s41467-023-41484-3.
Jiaoling Chen # 1,  Yaxing Bai # 1,  Ke Xue 1,  Zhiguo Li 1,  Zhenlai Zhu 1,  Qingyang Li 1,  Chen Yu 1,  Bing Li 1,  Shengxian Shen 1,  Pei Qiao 1,  Caixia Li 1,  Yixin Luo 1,  Hongjiang Qiao 1,  Erle Dang 1,  Wen Yin 2,  Johann E Gudjonsson 3,  Gang Wang 4,  Shuai Shao 5
Affiliations

Affiliations

  • 1 Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
  • 2 Department of Transfusion Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
  • 3 Department of Dermatology, University of Michigan, Ann Arbor, MI, 48109, USA. johanng@med.umich.edu.
  • 4 Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China. wanggangxjyy@163.com.
  • 5 Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China. shaoshuai19900728@qq.com.
  • # Contributed equally.
PMID: 37736772 DOI: 10.1038/s41467-023-41484-3
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.

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