PIEZO1 mediates mechanical reprogramming of neutrophils for proangiogenic specialization in the lung
Jin Wang, … , Bin Li, Jing Wang
Jin Wang, … , Bin Li, Jing Wang
Published June 2, 2025
Citation Information: J Clin Invest. 2025;135(11):e183796. https://doi.org/10.1172/JCI183796.
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Research Article Immunology Pulmonology Vascular biology

PIEZO1 mediates mechanical reprogramming of neutrophils for proangiogenic specialization in the lung

Abstract

Neutrophils are the most abundant immune cells that constantly patrol or marginate inside vascular beds to support immune homeostasis. The extent to which neutrophils undergo reprogramming in response to the changes in vascular architecture and the resultant biological implications of such adaptations remain unclear. Here, we performed intravital imaging and transcriptional profiling to investigate neutrophil behavior across different tissues. Our findings revealed that neutrophils had significant deformability and spontaneous calcium signaling while navigating through the narrow pulmonary vessels. Pulmonary neutrophils exhibited unique transcriptional profiles and were specialized for proangiogenic functions. We found that the mechanosensitive ion channel Piezo-type mechanosensitive ion channel component 1 (PIEZO1) was essential for neutrophil reprogramming. Deletion of Piezo1 in neutrophils ablated the lung-specific proangiogenic transcriptional signature and impaired capillary angiogenesis in both physiological and pathological conditions. Collectively, these data show that mechanical adaptation of neutrophils within the pulmonary vasculature drives their reprogramming in the lungs and promotes pulmonary vascular homeostasis.

Authors

Jin Wang, Wenying Zhao, Wenjuan Bai, Dong Dong, Hui Wang, Xin Qi, Ajitha Thanabalasuriar, Youqiong Ye, Tian-le Xu, Hecheng Li, Paul Kubes, Bin Li, Jing Wang

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Figure 2

Neutrophils display lung-specific signaling and transcriptome under normal conditions.

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Neutrophils display lung-specific signaling and transcriptome under norm...
(A) Construction strategy of neutrophil calcium reporter mice. (B) Time-lapse images showing a single calcium event in neutrophils in the lung. Scale bars: 30 μm. (C) MFI time plot of neutrophil displaying a short Ca2+ transient. Images of the Ca2+ signals of the cells are transposed onto the plots. (D) MFI time plot of neutrophil displaying no Ca2+ signal. (E) Frequency of Ca2+ signals in neutrophils from different tissues. Data were calculated as the percentage of neutrophils displaying Ca2+ in total neutrophils during the same recording time. n = 5 mice. (F) Correlation between the G/R ratio and sphericity of neutrophils in vivo. (G) Total transcripts of sorted BM, lung, and PB neutrophils are presented in a PCA plot. n = 3 mice. (H) Venn diagram representing DEGs between lung and PB neutrophils. (I) Pathway analysis of DEGs between lung and PB neutrophils. (J) UMAP of 20,941 neutrophils from PB (9,118 neutrophils) and lung (11,823 neutrophils), colored by sample origin (upper panel) or cell type (lower panel). (K) Proportions of the 5 neutrophil clusters in lung and PB samples. (L) Heatmap showing row-scaled expression of top DEGs from scRNA-Seq data for each averaged tissue profile. Data in E indicate the mean ± SEM. Statistical significance was determined by 1-way ANOVA with Tukey’s multiple-comparison test.