Abstract

Pseudomonas aeruginosa (P. aeruginosa) is a leading cause of hospital- and ventilator-associated pneumonia, driven by virulence factors that damage lung tissue. Neutrophils and monocytes are myeloid immune cells that play key roles in host defense during pulmonary infection against P. aeruginosa; although if not properly regulated, their inflammatory activity can lead to severe lung injury. Thrombospondin-1 (TSP-1) is a host glycoprotein that regulates neutrophil activation in the lungs during P. aeruginosa infection, protecting the host from mortality. Here, we demonstrate that in addition to regulating the pro-inflammatory phenotype of neutrophils, during P. aeruginosa infection, TSP-1 induces IL-10 in the lung tissue of mice inoculated with this bacterium. Our data show that neutrophils and Ly6C+ monocytes are major sources of lung IL-10 during the first 48 h post-infection, a cytokine that is required for host survival, host defense, and to reduce lung inflammation and injury. Further in vitro studies determined that TSP-1 induces IL-10 production in lipopolysaccharide-stimulated CD11b+Ly6G+Ly6C+ cells differentiated from bone marrow precursors through a mechanism dependent on the transcription factor peroxisome proliferator-activated receptor gamma (PPAR gamma). Importantly, intratracheal transfer of IL-10+/+ CD11b+Ly6G+Ly6C+ cells 1 day before infection to Thbs1-/- mice restored their ability to produce IL-10 in the lungs, improved host defense, and reduced lung inflammation and permeability upon infection. Altogether, our data show that TSP-1 induces IL-10 production in neutrophils and monocytes, enhancing host defense while reducing lung inflammation.