PIEZO1 mediates mechanical reprogramming of neutrophils for proangiogenic specialization in the lung
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
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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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 3

PIEZO1 regulates pulmonary-specific neutrophil behavior and the transcriptome.

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PIEZO1 regulates pulmonary-specific neutrophil behavior and the transcri...
(A) Heatmap of normalized calcium fluorescence versus time for each BM neutrophil isolated from WT and Piezo1-cKO mice. (B) Frequency of Ca2+ signals in neutrophils, as assessed by intravital imaging of lungs from WT Salsa6f and Piezo1-cKO-Salsa6f mice. n = 5. (C) Migration trajectory of WT and Piezo1-cKO neutrophils in the lungs. Bars indicate track duration. (D) Distribution frequency of track duration and average track velocity of WT and Piezo1-cKO neutrophils in the lung. (E) PCA of gene expression data of neutrophils isolated from the blood and the lungs of WT and Piezo1-cKO mice. (F) Venn diagram showing the commonly upregulated genes across the specified comparisons. Genes with potential functional significance were selected, and their expression levels are presented in a heatmap. The value is z score calculated from scaling log2 (transcripts per million [TPM]) values. (G) Pathway analysis of DEGs between WT and Piezo1-cKO neutrophils in lung. Data in B indicate the mean ± SEM. Statistical significance was determined by unpaired, 2-tailed Student’s t test (B) and 2-sample Kolmogorov-Smirnov test (D).