Effect of Pseudomonas aeruginosa (WT and dFliC) infection on PMN- and M-MDSC

Pseudomonas aeruginosa (P.a.) is a pathogenic opportunistic bacterium, classified as a priority by the WHO for the research of new treatments. As this bacterium is harmful trough the inflammation and tissue damage it causes, we investigated the role of Myeloid Derived Suppressor Cells (MDSC) in P.a. infections and their potential as a therapeutic tool. Using both ‘classically’ obtained MDSC (through mice bone-marrow differentiation), and a new procedure developped here (using the ER-Hoxb8 hematopoietic cell line), we observed that after administering intra-nasally a lethal dose of P.a (PAO1), intra-pulmonary transfer of MDSC, in both prophylactic and therapeutic protocols, markedly improves survival of P.a infected animals. Mechanistically, with a sub-lethal dose of P.a, we observed that MDSC transfer modulated lung tissue injury, down-regulated inflammatory responses and elicited lung repair. We further showed that WT-PAO1 and MDSC (and their subtypes PMN-MDSC and M-MCSF) could interact directly in vitro and in vivo, and that both PMN- and M-MDSC gene expression (assessed through RNA sequencing) was modulated after in vitro P.a. infection, and that WT-PAO1 (but not dFlic-PAO1) infection led to inhibition of T cell proliferation and promoted epithelial cell wound healing. Furthermore, we showed that the transcription factor Nr4A1 was up-regulated in both PMN- and M-MDSC- infected cells and may be an important mediator in the process. Altogether, we highlight a potential beneficial role of MDSC in P.a. infection responses and suggest that the unique properties of MDSC make them attractive potential new therapeutic tools for patients with acute or chronic inflammatory diseases.