Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
Department of Transfusion Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
Nat Commun. 2023 Sep 22;14(1):5894. doi: 10.1038/s41467-023-41484-3.
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 neutrophils accumulate in the blood and inflamed skin in human psoriasis, and correlate with disease severity. Compared to CXCR4 neutrophils, CXCR4 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 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 neutrophil infiltration amplifies skin inflammation, whereas blockade of CXCR4 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 neutrophil development and characterizes the contribution of CXCR4 neutrophils to vascular remodeling and inflammatory responses in skin.
中性粒细胞通过释放促炎介质或中性粒细胞细胞外陷阱 (NETs) 在炎症中具有致病作用。然而，它们的异质性和促炎机制仍不清楚。在这里，我们证明了 CXCR4 中性粒细胞在人类银屑病的血液和炎症皮肤中积累，并与疾病严重程度相关。与 CXCR4 中性粒细胞相比，CXCR4 中性粒细胞在体外具有增强的 NETs 形成、吞噬功能、中性粒细胞脱颗粒作用以及促炎细胞因子和趋化因子的过度表达。这伴随着 CXCR4 中性粒细胞向糖酵解和乳酸释放的代谢转变，从而促进血管通透性和重塑。中性粒细胞中 CXCR4 的表达依赖于 CREB1，这是一种受 TNF 和 CXCL12 激活的转录因子，并受从头合成的调节。在体内，CXCR4 中性粒细胞浸润会放大皮肤炎症，而通过 CXCR4 或 CXCL12 抑制阻断 CXCR4 中性粒细胞会导致免疫反应受到抑制。在这项工作中，我们的研究确定了 CREB1 是 CXCR4 中性粒细胞发育的关键调节剂，并描述了 CXCR4 中性粒细胞对皮肤血管重塑和炎症反应的贡献。
