Progranulin deficiency suppresses allergic asthma and enhances efferocytosis via PPAR-γ/MFG-E8 regulation in macrophages.
Progranulin deficiency suppresses allergic asthma and enhances efferocytosis via PPAR-γ/MFG-E8 regulation in macrophages.
复制标题
DOI：
10.1002/iid3.779
复制
发表时间：
2023-03
影响因子：
3.2
通讯作者：
Xu, Wenchun
中科院分区：
文献类型：
--
作者：
Huang, Qi;Weng, Danlin;Yao, Shifei;Shen, Hailan;Gao, Song;Zhang, Yanyu;Huang, Wenjie;Wang, Yan;Wang, Hong;Xu, Wenchun
关键词：
在变应性哮喘中，胞吐作用可缓解气道炎症，增强气道耐受性。虽然先前的工作已经报道了颗粒蛋白前体（PGRN）调节巨噬细胞吞噬作用，但尚不清楚PGRN介导的巨噬细胞吞噬作用是否与哮喘相关。在这里，我们发现，在卵清蛋白（OVA）诱导的过敏性哮喘模型中，PGRN缺陷小鼠的气道炎症受到抑制，肺组织中的细胞凋亡得到改善。相反，在人支气管上皮细胞中PGRN敲低增加了体外细胞凋亡。此外，PGRN缺陷型巨噬细胞在体外和体内均具有比野生型（WT）巨噬细胞显著更强的巨噬细胞能力。PGRN缺陷型腹腔巨噬细胞（PM）表现出与嗜酸性粒细胞增多症相关的基因表达增加，包括乳脂球表皮生长因子8（MFG-E8）、过氧化物酶体增殖物激活受体γ（PPAR-γ）和沉默调节蛋白1（SIRT 1），以及嗜酸性粒细胞增多症期间产生抗炎介质白细胞介素（IL）-10的能力增加。GW9662（PPAR-γ抑制剂）可消除PGRN缺陷PM中增加的红细胞增多和MFG-E8表达，表明PGRN缺陷通过PPAR-γ增强MFG-E8介导的红细胞增多。相应地，在OVA诱导的PGRN缺陷小鼠的肺中，嗜酸性粒细胞增多症基因增加。GW9662治疗降低了MFG ‐ E8表达，但对气道炎症无显著影响。我们的研究结果表明，PGRN缺乏通过PPAR-γ/MFG-E8途径增强了细胞增殖，这可能是PGRN缺乏导致过敏性哮喘气道炎症抑制的原因之一。我们发现，颗粒蛋白前体（PGRN）缺乏可抵抗卵清蛋白诱导的小鼠过敏性哮喘，并通过过氧化物酶体增殖物激活受体γ/乳脂球-表皮生长因子8途径促进巨噬细胞吞噬。这些结果为PGRN影响过敏性哮喘的进展提供了新的证据。
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. we found that progranulin (PGRN) deficiency conferred resistance to ovalbumin‐induced allergic asthma in mice and facilitated macrophage efferocytosis via peroxisome proliferator‐activated receptor gamma/milk fat globule‐epidermal growth factor 8 pathway. These results provide new evidence that PGRN influences the progression of allergic asthma.
登录
查看更多内容
DOI：
10.1016/j.jaci.2018.01.029
发表时间：
2018-12
期刊：
The Journal of allergy and clinical immunology
影响因子：
--
作者：
Felton JM;Lucas CD;Dorward DA;Duffin R;Kipari T;Vermeren S;Robb CT;MacLeod KG;Serrels B;Schwarze J;Haslett C;Dransfield I;Rossi AG
通讯作者：
Rossi AG
影响因子：
3.1
作者：
Cho IH;Gong JH;Kang MK;Lee EJ;Park JH;Park SJ;Kang YH
通讯作者：
Kang YH
影响因子：
14.9
作者：
Han L;Zhou R;Niu J;McNutt MA;Wang P;Tong T
通讯作者：
Tong T
影响因子：
9
作者：
Hwang JS;Lee WJ;Kang ES;Ham SA;Yoo T;Paek KS;Lim DS;Do JT;Seo HG
通讯作者：
Seo HG
玻染蛋白通过与凋亡细胞以及巨噬细胞的相互作用来抑制胚细胞增多症。
DOI：
10.4049/jimmunol.1200625
发表时间：
2013-03-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Bae HB;Tadie JM;Jiang S;Park DW;Bell CP;Thompson LC;Peterson CB;Thannickal VJ;Abraham E;Zmijewski JW
通讯作者：
Zmijewski JW