PROK2定义了致病性中性粒细胞亚群，并作为慢性阻塞性肺病中性粒细胞炎症的临床指标
PROK2 defines a pathogenic neutrophil subset and serves as a clinical indicator of neutrophilic inflammation in COPD.
摘要(中文译文)
目的：慢性阻塞性肺疾病（COPD）是一种以进行性气流受限为特征的慢性炎症性肺部疾病。然而，其关键致病性免疫细胞亚群仍不清楚。方法：建立香烟烟雾诱导的COPD小鼠模型。采用单细胞RNA测序（scRNA-seq）和流式细胞术表征肺部免疫细胞的组成、表型状态及细胞间通讯。通过多重免疫荧光及ELISA在小鼠和COPD患者中验证PROK2及炎症介质。结果：长期香烟烟雾（CS）暴露导致COPD及以中性粒细胞为主的免疫重塑。值得注意的是，一个中性粒细胞亚群——PROK2⁺中性粒细胞（Neu-PROK2）成为优势中性粒细胞群体，并表现出基质金属蛋白酶（MMPs）、NADPH氧化酶组分及中性粒细胞胞外诱捕网相关基因表达升高，在CS暴露下促进组织损伤。多重免疫荧光还显示PROK2主要定位于CS肺组织的肺泡LY6G⁺中性粒细胞中。此外，Neu-PROK2包含一个中间型Ltf lo储库和一个终末型高炎症Ltf hi状态，形成由CS驱动的连续谱，从Neu-PROK2 Ltf lo向Ltf hi进展，FOSL1作为上游驱动因子。重要的是，稳定期COPD患者血清PROK2升高，与中性粒细胞相关炎症/NET标志物呈正相关，与嗜酸性粒细胞分层及肺功能呈负相关。结论：本研究提出PROK2⁺中性粒细胞是COPD中关键致病性中性粒细胞亚群，并推测FOSL1为潜在上游驱动因子。这些发现提示PROK2可能作为与COPD中性粒细胞相关炎症活动有关的候选循环生物标志物。
Abstract
PURPOSE: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease with progressive airflow limitation. However, the key pathogenic immune cell subset remains unknown. METHODS: A cigarette smoke-induced COPD mouse model was established. The composition, phenotypic state, and intercellular communication of immune cells in the lungs were characterized using scRNA-seq and flow cytometry. PROK2 and inflammatory mediators were validated by multiplex immunofluorescence and by ELISA in mice and patients with COPD. RESULTS: Chronic cigarette smoke (CS) exposure caused COPD and neutrophil-dominant immune remodeling. Notably, a neutrophil subset, PROK2+ neutrophils (Neu-PROK2), became the dominant neutrophil population, and exhibited elevated expression of matrix metalloproteinases (MMPs), NADPH oxidase components, and neutrophil extracellular traps-related genes, contributing to tissue injury under CS. Multiplex immunofluorescence also revealed PROK2 was primarily localized in alveolar LY6G⁺ neutrophils in CS lungs. Furthermore, Neu-PROK2 comprised an intermediate Ltf lo reservoir and a terminal hyperinflammatory Ltf hi state, forming a CS-driven continuum that progresses from Neu-PROK2 Ltf lo toward Ltf hi, with FOSL1 acting as an upstream driver. Importantly, Serum PROK2 was elevated in stable COPD, correlated positively with neutrophil-associated inflammatory/NET markers, and was inversely associated with eosinophil strata and lung function. CONCLUSION: Our study nominates PROK2⁺ neutrophils as a key pathogenic neutrophil subset in COPD and posits FOSL1 as a putative upstream driver. These findings suggest that PROK2 may serve as a candidate circulating biomarker associated with neutrophil-related inflammatory activity in COPD.
如何引用
AMA
Renming Li, Chen Cheng, Xueqin Zhao, Hu Xu, Yuqing Fei, Siguo Zhao, et al. PROK2 defines a pathogenic neutrophil subset and serves as a clinical indicator of neutrophilic inflammation in COPD.. Respiratory research. 2026; doi:10.1186/s12931-026-03679-2.
APA
Renming Li, Chen Cheng, Xueqin Zhao, Hu Xu, Yuqing Fei, Siguo Zhao, et al (2026). PROK2 defines a pathogenic neutrophil subset and serves as a clinical indicator of neutrophilic inflammation in COPD.. Respiratory research. https://doi.org/10.1186/s12931-026-03679-2
GB/T 7714
Renming Li, Chen Cheng, Xueqin Zhao, Hu Xu, Yuqing Fei, Siguo Zhao, et al. PROK2 defines a pathogenic neutrophil subset and serves as a clinical indicator of neutrophilic inflammation in COPD.[J]. Respiratory research, 2026 doi:10.1186/s12931-026-03679-2.
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