Abstract
Efferocytosis can resolve airway inflammation and enhance airway tolerance in allergic asthma. While previous work has reported that progranulin (PGRN) regulated macrophage efferocytosis, but it is unclear whether PGRN-mediated efferocytosis is associated with asthma. Here, we found that in an ovalbumin (OVA)-induced allergic asthma model, the airway inflammation was suppressed and the apoptosis in lung tissues was ameliorated in PGRN-deficient mice. In contrast, PGRN knockdown in human bronchial epithelial cells increased apoptosis in vitro. Furthermore, PGRN-deficient macrophages had significantly stronger efferocytosis ability than wild type (WT) macrophages both in vitro and in vivo. PGRN-deficient peritoneal macrophages (PMs) exhibited increased expression of genes associated with efferocytosis including milk fat globule-epidermal growth factor 8 (MFG-E8), peroxisome proliferator-activated receptor gamma (PPAR-γ) and sirtuin1 (SIRT1) and increased capacity to produce the anti-inflammatory mediator interleukin (IL)-10 during efferocytosis. GW9662, the inhibitor of PPAR-γ, abolished increased efferocytosis and MFG-E8 expression in PGRN-deficient PMs suggesting that PGRN deficiency enhanced MFG-E8-mediated efferocytosis through PPAR-γ. Correspondingly, efferocytosis genes were increased in the lungs of OVA-induced PGRN-deficient mice. GW9662 treatment reduced MFG-E8 expression but did not significantly affect airway inflammation. Our results demonstrated that PGRN deficiency enhanced efferocytosis via the PPAR-γ/MFG-E8 pathway and this may be one of the reasons PGRN deficiency results in inhibition of airway inflammation in allergic asthma.