Human M-MDSCs impair neutrophil migration in the infectious microenvironment

Patients who survive sepsis experience a prolonged period of immunosuppression. This period is accompanied by the expansion of monocytic myeloid-derived suppressor cells (M-MDSCs), a subset of suppressive myeloid cells; however, the impact of M-MDSCs on the innate immune response to infection is not well understood. Here we investigate the effect of MDSCs on neutrophils, a critical component of the innate immune response, during bacterial infection. We found that M-MDSCs, differentiated from monocytes in vitro, impaired neutrophil chemotaxis to IL-8 in a simple microfluidic chemotactic device. We then integrated M-MDSCs and neutrophils into our 3D infection-on-a-chip device that incorporates key features of an infectious environment including an endothelial lumen, a collagen extracellular matrix, and a source of Pseudomonas aeruginosa. When M-MDSCs were present in the matrix during simulated infection with Pseudomonas aeruginosa, significantly fewer neutrophils extravasated from the lumen, and those that left traveled a shorter distance from the lumen edge. We found IL-10 secretion increased during infections in the presence of M-MDSCs and blocking IL-10 restored neutrophil extravasation, indicating IL-10 secretion reduces neutrophil extravasation in the presence of M-MDSCs. In summary, we demonstrated impaired neutrophil chemotaxis, extravasation, and migration in the presence of M-MDSCs during bacterial infection and found increased levels of IL-10 contribute to reduced extravasation, indicating that MDSCs play a role in regulating the immune environment, leading to a reduced neutrophil response to infection.