Intrapulmonary-administered myeloid derived suppressor cells rescue mice from Pseudomonas aeruginosa infection and promote a regulatory/repair phenotype.

Abstract

Pseudomonas aeruginosa (P.aeruginosa) is a pathogenic opportunistic bacterium, classified as a priority by the WHO for the research of new treatments. As this bacterium is harmful through the inflammation and tissue damage it causes, we investigated the role of Myeloid Derived Suppressor Cells (MDSC) in P.aeruginosa infections and their potential as a therapeutic tool. Using both 'classically' obtained MDSC (through mice bone-marrow differentiation), and a new procedure developed here (using the ER-Hoxb8 hematopoietic cell line), we observed that after administering intra-nasally a lethal dose of P.aeruginosa (PAO1), intra-pulmonary transfer of MDSC, in both prophylactic and therapeutic protocols, markedly improves survival of P.aeruginosa infected animals. Mechanistically, with a sub-lethal dose of P.aeruginosa, 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.aeruginosa infection, and that WT-PAO1 (but not ΔFlic-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.aeruginosa 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.