Lysyl Oxidase Reduces Neutrophil Extravasation in Response to P. aeruginosa in an Infection-on-a-Chip Model

Abstract

Neutrophils are crucial players in the fight against infections. Unfortunately, dysregulated neutrophil function contributes to the pathogenesis of diseases, including cancer, fibrosis, and atherosclerosis, that leave those afflicted vulnerable to severe infections. Many of these diseases are accompanied by differential lysyl oxidase (LOX) activity. The LOX enzyme crosslinks collagen and elastin, two highly expressed proteins in the extracellular matrix (ECM), altering the ECM's mechanical properties. While it is known ECM mechanical properties regulate neutrophil function, the role of LOX crosslinking of collagen on the neutrophil response is unclear. This study uses a microfluidic “infection-on-a-chip”. This device consists of a model blood vessel endothelium embedded in an ECM mimic to investigate how LOX crosslinking of collagen affects neutrophil function in response to infection. Interestingly, LOX-crosslinking of collagen decreases neutrophil extravasation through an endothelium in response to Pseudomonas aeruginosa compared to uncrosslinked collagen hydrogels. Critically, endothelial cells in devices with LOX-crosslinked collagen exhibited increased VE-cadherin expression compared to those seeded in uncrosslinked collagen gels, which is hypothesized to restrict neutrophil extravasation. These data demonstrate the regulatory capability of LOX over the neutrophil response, providing a potential therapeutic pathway for diseases associated with neutrophil dysregulation and LOX activity that merits further investigation.