Human M-MDSCs impair neutrophil migration in the infectious microenvironment

Area of Science:

• Immunology
• Infectious Disease
• Cell Biology

Background:

• Sepsis survivors face prolonged immunosuppression linked to monocytic myeloid-derived suppressor cells (M-MDSCs).
• The precise role of M-MDSCs in modulating the innate immune response to infection remains unclear.

Purpose of the Study:

• To investigate the impact of M-MDSCs on neutrophil function during bacterial infection.
• To elucidate the mechanisms by which M-MDSCs affect neutrophil chemotaxis and extravasation.

Main Methods:

• Utilized microfluidic devices to assess neutrophil chemotaxis towards IL-8 in the presence of M-MDSCs.
• Developed a 3D infection-on-a-chip model simulating Pseudomonas aeruginosa infection with neutrophils and M-MDSCs within an endothelial lumen and collagen matrix.
• Measured neutrophil extravasation, migration, and IL-10 secretion levels.

Main Results:

• M-MDSCs impaired neutrophil chemotaxis to IL-8 in vitro.
• In the 3D infection model, M-MDSCs significantly reduced neutrophil extravasation and migration from the lumen during Pseudomonas aeruginosa infection.
• Increased IL-10 secretion was observed in the presence of M-MDSCs, and blocking IL-10 restored neutrophil extravasation.

Conclusions:

• M-MDSCs inhibit critical neutrophil functions, including chemotaxis and extravasation, during bacterial infections.
• Elevated IL-10 levels secreted by M-MDSCs contribute to the suppression of neutrophil recruitment.
• MDSCs play a significant role in regulating the immune microenvironment, leading to a diminished neutrophil response during infection.