Monocytic myeloid-derived suppressor cells mediate the resolution of lung ischemiareperfusion injury via MerTK-dependent efferocytosis

Abstract Ischemia-reperfusion injury (IRI) after lung transplantation results in primary graft dysfunction leading to acute and chronic graft rejection. We investigated the role of monocytic myeloid-derived suppressor cells (M-MDSCs) to mediate inflammation-resolution of lung IRI. A murine model of lung hilar ligation was used in Balb/c (WT) and cebpβ −/−(M-MDSC deficient) mice. Lung function, inflammation and M-MDSC infiltration were assessed after 6- or 24hrs in mice undergoing sham control or IRI surgeries. CD11b +Ly6G −Ly6C +iNOS +M-MDSC lung infiltration in WT mice was significantly increased after 24hrs of IRI compared to 6hrs of IRI (9.9×10 3±1.2×10 3vs. 6.5×10 3±0.4×10 3; p=0.02; n=8/group), The upregulation of M-MDSC infiltration at 24hrs was accompanied by increased pulmonary compliance (5.3±0.2 vs. 2.9±0.1 μl/cm H 2O; p<0.0001; n=12/group), decreased neutrophil infiltration as well as decreased pro-inflammatory IL-17, TNF-α, and CXCL1 secretion compared to 6hrs of lung IRI. The resolution of lung IRI at 24hrs was blocked in cebpβ −/−mice compared to Balb/c mice as demonstrated by decreased pulmonary compliance (3.1±0.1 vs. 5.3±0.2 μl/cm H 2O; p<0.0001; n=7–12/group), that was accompanied by a decrease in M-MDSC lung infiltration (3.3×10 3±0.20×10 3vs. 9.9×10 3±1.2×10 3; p=0.003; n=5–8/group). In vitro analysis using a hypoxia-reoxygenation model of lung IRI displayed an increase in efferocytosis as shown by M-MDSC-dependent uptake of apoptotic neutrophils as well as alveolar epithelial cells via a MerTK-dependent mechanism, Collectively, our results indicate that lung IRI entails dysregulated inflammation-resolution which can be mitigated by M-MDSC-mediated MerTK-dependent efferocytosis.