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bioRxiv · 10.1101/2024.10.17.618860

Neutrophils exhibit distinct migration phenotypes that are modulated by transendothelial migration

Schwartz, A. B.·Kadasamy, A.·del Alamo, J. C.·Yeh, Y.-T.
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Abstract

The extravasation of polymorphonuclear neutrophils (PMNs) is a critical component of the innate immune response that involves transendothelial migration (TEM) and interstitial migration. TEM-mediated interactions between PMNs and vascular endothelial cells (VECs) trigger a cascade of biochemical and mechanobiological signals whose effects on interstitial migration are currently unclear. To address this question, we cultured human VECs on a fibronectin-treated transwell insert to model the endothelium and basement membrane, loaded PMN-like differentiated HL60 (dHL-60) cells in the upper chamber of the insert, and collected the PMNs that crossed the membrane-supported monolayer from the lower chamber. The 3D chemotactic migration of the TEM-conditioned PMNs through collagen matrices was then quantified. Data collected from over 50,000 trajectories showed two distinct migratory phenotypes, i.e., a high-persistence phenotype and a low-persistence phenotype. These phenotypes were conserved across treatment conditions, and their existence was confirmed in human primary PMNs. The high-persistence phenotype was characterized by more straight trajectories and faster migration speeds, whereas the low-persistence one exhibited more frequent sharp turns and loitering periods. A key finding of our study is that TEM induced a phenotypic shift in PMNs from high-persistence migration to low-persistence migration. Changes in the relative proportion of high-persistence and low-persistence populations correlated with GRK2 expression levels. Inhibiting GRK2 hindered the TEM-induced shift in migratory phenotype and impaired the phagocytic function of PMNs. Overall, our study suggests that TEM-mediated GRK2 signaling primes PMNs for a migration phenotype better suited for spatial exploration and inflammation resolution. These observations provide novel insight into the biophysical impacts of TEM that priming PMNs is essential to conduct sentinel functions.

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Schwartz, A. B., Kadasamy, A., del Alamo, J. C., Yeh, Y.-T.. 2024-10-17. Neutrophils exhibit distinct migration phenotypes that are modulated by transendothelial migration. https://doi.org/10.1101/2024.10.17.618860

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