Lymphatic endothelial cells regulate neutrophil phenotypes and function in a microphysiological model of infection
4 affiliations
- 1Department of Comparative Biomedical Sciences, University of Wisconsin-Madison, Madison, 53706 USA
- 2Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, 53705 USA
- 3Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, 53706 USA
- 4Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, 53705 USA
Abstract
Early skin inflammation requires coordinated immune regulation, with neutrophils acting as first-line responders. While the blood vasculature and its role in neutrophil recruitment during infection has been extensively studied, the lymphatic system remains comparatively understudied despite its known role in immune cell trafficking. Growing evidence suggests lymphatic vessels actively participate in regulating inflammatory responses, yet whether they coordinate neutrophil behavior during skin infection remains unclear. Staphylococcus aureus is particularly problematic in this context, employing multiple immune evasion strategies and representing a major driver of antibiotic-resistant skin and soft tissue infections worldwide. To address this gap, we developed a human-based 3D microphysiological system incorporating luminal lymphatic endothelial vessels, a collagen matrix and bacteria to model an infected microenvironment. We evaluated neutrophil migration, phagocytosis and NETosis in response to Escherichia coli and S. aureus. Lymphatic endothelium amplified neutrophil migration in a bacterial-dependent manner, with E. coli promoting directional migration toward the vessel while S. aureus suppressed migration and directionality despite increased phagocytic uptake. S. aureus also induced myeloperoxidase-positive NETs with nuclear morphology consistent with vital NETosis, rescued by DNase treatment. To our knowledge, this study provides the first evidence that lymphatic endothelium establishes a microenvironment that supports neutrophil responses to bacterial cues during skin infection.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1038/s41598-026-63432-z.
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BibTeX
@article{sholty2026lymphatic,
title = {{Lymphatic endothelial cells regulate neutrophil phenotypes and function in a microphysiological model of infection}},
author = {Kelsea A. Sholty and Sheena C. Kerr and David J. Beebe},
journal = {Scientific Reports},
year = {2026},
month = aug,
doi = {10.1038/s41598-026-63432-z},
url = {https://doi.org/10.1038/s41598-026-63432-z},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Lymphatic endothelial cells regulate neutrophil phenotypes and function in a microphysiological model of infection
AU - Kelsea A. Sholty
AU - Sheena C. Kerr
AU - David J. Beebe
PY - 2026
DA - 2026/08/02
JO - Scientific Reports
DO - 10.1038/s41598-026-63432-z
UR - https://doi.org/10.1038/s41598-026-63432-z
AB - Early skin inflammation requires coordinated immune regulation, with neutrophils acting as first-line responders. While the blood vasculature and its role in neutrophil recruitment during infection has been extensively studied, the lymphatic system remains comparatively understudied despite its known role in immune cell trafficking. Growing evidence suggests lymphatic vessels actively participate in regulating inflammatory responses, yet whether they coordinate neutrophil behavior during skin infection remains unclear. Staphylococcus aureus is particularly problematic in this context, employing multiple immune evasion strategies and representing a major driver of antibiotic-resistant skin and soft tissue infections worldwide. To address this gap, we developed a human-based 3D microphysiological system incorporating luminal lymphatic endothelial vessels, a collagen matrix and bacteria to model an infected microenvironment. We evaluated neutrophil migration, phagocytosis and NETosis in response to Escherichia coli and S. aureus. Lymphatic endothelium amplified neutrophil migration in a bacterial-dependent manner, with E. coli promoting directional migration toward the vessel while S. aureus suppressed migration and directionality despite increased phagocytic uptake. S. aureus also induced myeloperoxidase-positive NETs with nuclear morphology consistent with vital NETosis, rescued by DNase treatment. To our knowledge, this study provides the first evidence that lymphatic endothelium establishes a microenvironment that supports neutrophil responses to bacterial cues during skin infection. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1038/s41598-026-63432-z.
SN - 2045-2322
ER -