A role for IL-10 in efferocytosis of apoptotic neutrophils and resolution of lung inflammation produced by STAT1-regulated lung MDSC-like cells (P4255)

Abstract Bacterial pneumonia remains a significant burden worldwide. Little is known about cellular and molecular mechanisms in the lung tissue that remove apoptotic neutrophils to prevent collateral tissue damage during bacterial infection. In a mouse model of bacterial infection with Klebsiella pneumoniae, we observed a role for IL-10, produced in a highly orchestrated fashion by tissue-resident cells, in resolution of pulmonary inflammation and recovery of mice post-infection. While IL-10-/- mice cleared bacteria, they displayed increased morbidity with progressive weight loss and persistent lung inflammation. The major source of tissue IL-10 was CD11b+Gr1intF4/80+ cells resembling myeloid-derived suppressor cells (MDSCs) that accumulated with a delayed kinetics in the lung tissue after infection and efficiently efferocytosed apoptotic neutrophils. However, increased bacterial burden handicapped this function by decreasing the ratio of the efferocytic MDSC-like cells:inflammatory neutrophiils in the lung. To overcome this undesirable outcome, we took advantage of functional antagonism between STAT1 and STAT3. In STAT1-/- mice, the excessive neutrophil infiltration in the lungs elicited by a high dose of K. pneumoniae was attenuated with concomitant increase in the frequency of the MDSC-like cells that expressed increased pSTAT3 levels. Thus, inhibiting STAT1 may be a novel therapeutic strategy to address inefficient resolution of bacterial pneumonia.