Progranulin deficiency suppresses allergic asthma and enhances efferocytosis via PPAR‐γ/MFG‐E8 regulation in macrophages

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.

The role of deacetylase SIRT1 in allergic diseases

“…PPAR-γ plays an important role in the inflammatory response, inducing the oxidative metabolism of macrophages by upregulating the oxidation of fatty acids and mitochondrial biosynthesis ( 32 ). PPAR-γ increased the expression of SIRT1 in macrophages and upregulated SIRT1 increased the secretion of IL-10, thus playing an anti-inflammatory role ( 33 ).…”

“…Recent reports have explored treatment options for allergic inflammation, including drugs that target SIRT1 to provide relief for allergic diseases ( Table 1 ). Among the drugs that have demonstrated effectiveness in alleviating AAI are Allopurinol, GW9962, Hylocereus undatus flower (HUF), Pterostilbene (Pts), Gentiopicroside (GPS), and EX-527 ( 26 , 33 , 43 , 51 , 112 , 113 ). Studies have found that SIRT1 expression in immune cells can help relieve allergic rhinitis, and the use of SIRT1 agonist resveratrol has shown promise in treating AR ( 64 , 71 ).…”

Macrophages Orchestrate Airway Inflammation, Remodeling, and Resolution in Asthma

“…Apoptotic eosinophils and neutrophils are common in asthma [ 185 ]. Efferocytosis is a process that removes apoptotic cells during the inflammatory resolution stage and is essential for returning the lung to homeostasis [ 186 ]. Defective efferocytosis has been linked to secondary necrosis and release of damage signals that further enhance inflammation [ 185 , 187 ].…”

Efferocytosis and Respiratory Disease

“…The accumulated apoptotic cells suppressed the release of anti-inflammatory mediators such as IL-10 and TGF-β. And the shedding of Axl was also related to the damage of efferocytosis, while IFN could restore the expression of Axl on airway macrophages [107][108][109]. Research has shown that the expression of Neurofibroin-2 (Nrp2) is increased in neutrophil asthma mice and is a negative regulatory factor for neutrophil asthma.…”