Abstract Pseudomonas aeruginosa (PA) is a major cause of acute and chronic pulmonary infection globally and one of the 5 bacterial species that by 2019 caused 7% of the global mortality. The expression of multiple virulence factors PA causes a proteolytic pneumonia associated with elevated injury and high mortality due to antimicrobial resistance and limited therapeutic tools available.Thrombospondin-1 (TSP1) is a host glycoprotein that downregulates lung neutrophil pro-inflammatory activation during acute infection. In the current work, we demonstrate that TSP-1 does not only downmodulate the pro-inflammatory activation of neutrophils, but it also induces the production of IL-10 by these cells during the first 48 hours post infection in the lungs. Using in vivo models of infection, we determined that IL-10 regulates lung inflammation, host defense and survival. In addition, we demonstrate in vitro that TSP1 directly triggers IL-10 production in differentiated neutrophils in a mechanism dependent on the transcription factor peroxisome proliferator-activated receptor gamma (PPARγ).Finally, we show that intratracheal transfer of neutrophils capable to produce IL-10 one day prior infection restores the production of lung IL-10 in Thbs-1-/- mice, improves lung bacterial clearance and reduces pro-inflammatory cytokine production.This data provides novel insight regarding the downstream regulation of the inflammatory response by TSP-1 that involves the production of IL-10 by neutrophils, immune cells that traditionally have been labeled as pro-inflammatory cells. In addition, it demonstrates the therapeutic potential of cell therapy to patients with reduced TSP1 and/or IL-10 expression that are infected with PA. This abstract is funded by: Agencia Nacional de Investigación y Desarrollo
Peñaloza et al. (Fri,) studied this question.