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

作者：Jiaoling Chen, Yaxing Bai, Ke Xue, Zhiguo Li, Zhenlai Zhu, Qingyang Li, Yu Chen, Bing Li, Shengxian Shen, Pei Qiao, Caixia Li, Yixin Luo, Hongjiang Qiao, Erle Dang, Wen Yin, Jóhann E. Guðjónsson, Gang Wang, Shuai Shao · 发表于：Nature Communications · 年份：2023 · DOI：10.1038/s41467-023-41484-3 · 被引用次数：85 · 研究领域：Neutrophil, Myeloperoxidase and Oxidative Mechanisms、Psoriasis: Treatment and Pathogenesis、Atherosclerosis and Cardiovascular Diseases

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 CXCR4 hi neutrophils accumulate in the blood and inflamed skin in human psoriasis, and correlate with disease severity. Compared to CXCR4 lo neutrophils, CXCR4 hi 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 CXCR4 hi 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, CXCR4 hi neutrophil infiltration amplifies skin inflammation, whereas blockade of CXCR4 hi neutrophils through CXCR4 or CXCL12 inhibition leads to suppression of immune responses. In this work, our study identifies CREB1 as a critical regulator of CXCR4 hi neutrophil development and characterizes the contribution of CXCR4 hi neutrophils to vascular remodeling and inflammatory responses in skin.