Neutrophilic myeloid derived immunosuppressive cells (MDSC) promote granuloma formation by specifically producing Osteopontin in lung granulomatous diseases

Numerous neutrophils populate the lung after particle inhalation. Their exact function and polarization remains, however, to be elucidated. In this study, we demonstrate that pulmonary neutrophils recruited upon silica or carbon nanotubes (CNT) inhalation are phenotypically and functionally distinct from classical inflammatory neutrophils. Particle-induced neutrophils possess the ability to suppress the activation of T lymphocytes, do not express the inflammatory neutrophil markers NGP (Neutrophil Granule Protein) and CXCR2 and can be defined as N-MDSC (Neutrophil Myeloid Immunosuppressive Cells). We also show that interleukin (IL)-1 α and β elicit the accumulation of N-MDSC in the lung of silica- or CNT-treated mice. N-MDSC specifically express osteopontin and M-CSF that mediate the differentiation of suppressive M2-macrophages. Gemcitabine prevents N-MDSC influx and reduces particle-induced lung granuloma development by limiting M2-macrophage differentiation and accumulation. Our data indicate that targeting the expansion of N-MDSC and their suppressive mediators represents a new strategy for limiting particle-induced granulomatous disease.