Interleukin-6 regulates the neutrophil response to diverse bacteria

Neutrophils are critical mediators of the innate immune response, and their antimicrobial functions are tightly regulated by a myriad of cytokines. Interleukin-6 (IL-6) is known to be essential for an effective immune response; however, how varying IL-6 concentrations affect the neutrophil response remains poorly understood. Because IL-6 concentrations can vary greatly across different disease states, we investigated the concentration dependent effects of IL-6 on the neutrophil response to diverse bacterial pathogens using an infection-on-a-chip microfluidic device. We found that a high exogenous IL-6 concentration (100 ng/mL) reduced neutrophil extravasation, migration speed, and displacement compared to conditions without exogenous IL-6. In contrast, a lower exogenous IL-6 concentration (10 ng/mL) produced pathogen-specific effects on neutrophil extravasation: exogenous IL-6 increased neutrophil extravasation in response to <i>Pseudomonas aeruginosa</i>, did not change in response to <i>Listeria monocytogenes</i>, and decreased in response to <i>Staphylococcus aureus</i> relative to controls. We then determined the potential endothelial cell contributions to these responses. We found that increasing IL-6 concentration resulted in decreased VE-cadherin expression and that 100 ng/mL exogenous IL-6 resulted in lower ICAM-1 expression than 10 ng/mL exogenous IL-6 in an endothelium exposed to <i>P. aeruginosa</i>. Together, these results demonstrate that IL-6 exerts concentration- and pathogen-dependent effects on neutrophil recruitment and migration, supporting a dual role for IL-6 as both pro-inflammatory and anti-inflammatory, with higher IL-6 concentrations resulting in a more anti-inflammatory neutrophil response.