Lymphatic Endothelial Cells Regulate Neutrophil Phenotypes and Function in a Microphysiological Model of Infection.

Area of Science:

• Immunology
• Vascular Biology
• Microbiology

Background:

• Neutrophils are key responders in early skin inflammation.
• The lymphatic system's role in regulating inflammatory responses and neutrophil behavior during skin infection is understudied.
• Staphylococcus aureus poses a significant challenge due to its immune evasion strategies and contribution to antibiotic-resistant infections.

Purpose of the Study:

• To investigate the role of lymphatic endothelium in coordinating neutrophil behavior during skin infection.
• To model an infected microenvironment using a human-based 3D microphysiological system.
• To compare neutrophil responses to Escherichia coli and Staphylococcus aureus within this model.

Main Methods:

• Development of a 3D microphysiological system with human lymphatic endothelial vessels, collagen matrix, and bacteria.
• Evaluation of neutrophil migration, phagocytosis, and NETosis (neutrophil extracellular trap formation).
• Assessment of responses to both Escherichia coli and Staphylococcus aureus.

Main Results:

• Lymphatic endothelium amplified neutrophil migration in a manner dependent on the bacteria present.
• Escherichia coli promoted directional neutrophil migration toward the lymphatic vessel.
• Staphylococcus aureus suppressed neutrophil migration and directionality, despite increasing phagocytic uptake, and induced vital NETosis.

Conclusions:

• This study demonstrates for the first time that lymphatic endothelium directly influences neutrophil behavior during skin infection.
• The lymphatic system plays a complex role, differentially regulating neutrophil responses based on the specific bacterial pathogen.
• Lymphatic vessels are active participants in modulating the immune response to bacterial skin infections.