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AMFR 通过促进肺泡巨噬细胞衍生的 GM-CSF 产生来驱动过敏性哮喘的发展。

AMFR drives allergic asthma development by promoting alveolar macrophage-derived GM-CSF production.

机构信息

Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, Pharm-X Center, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, P.R. China.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China.

出版信息

J Exp Med. 2022 May 2;219(5). doi: 10.1084/jem.20211828. Epub 2022 Mar 25.

DOI:10.1084/jem.20211828
PMID:35333296
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8961293/
Abstract

Alveolar macrophages (AMs) are specialized tissue-resident macrophages that orchestrate the immune response in allergic inflammation and asthma. However, what signals direct AMs to cross talk with other immune cells remains unclear. Here, we report that autocrine motility factor receptor (AMFR), an endoplasmic reticulum-resident E3 ubiquitin ligase, is upregulated in AMs of asthma and is critical for this condition. AMFR deficiency significantly decreased allergy-induced T helper 2 (Th2) and eosinophilic inflammation, with less granulocyte-macrophage colony-stimulating factor (GM-CSF) production in AMs. Mechanistically, following thymic stromal lymphopoietin (TSLP) stimulation, AMFR associated directly with cytokine-inducible SH2-containing protein (CIS), induced the ubiquitination of Lys48-linked polyubiquitination of CIS, and consequently blocked the inhibitory effect of CIS on signal transducer and activator of transcription 5 (STAT5) phosphorylation and the downstream pathway activation in AMs. In conclusion, our results demonstrate that AMFR serves a crucial role in promoting inflammation in asthma through regulating AM function, and may emerge as a new potential drug target for asthma therapy.

摘要

肺泡巨噬细胞 (AMs) 是一种特化的组织驻留巨噬细胞，在过敏炎症和哮喘中协调免疫反应。然而，指导 AMs 与其他免疫细胞相互交流的信号仍然不清楚。在这里，我们报告内质网驻留的 E3 泛素连接酶自分泌运动因子受体 (AMFR) 在哮喘的 AMs 中上调，并且对于这种情况至关重要。AMFR 缺乏显着降低了过敏诱导的 Th2 和嗜酸性粒细胞炎症，并且 AMs 中产生的粒细胞-巨噬细胞集落刺激因子 (GM-CSF) 减少。在机制上，在胸腺基质淋巴细胞生成素 (TSLP) 刺激后，AMFR 直接与细胞因子诱导的 SH2 结构域蛋白 (CIS) 相关，诱导 CIS 的 Lys48 连接多泛素化的泛素化，从而阻止 CIS 对信号转导和转录激活物 5 (STAT5) 磷酸化和 AMs 中下游途径激活的抑制作用。总之，我们的结果表明，AMFR 通过调节 AM 功能在哮喘中促进炎症中起关键作用，并且可能成为哮喘治疗的新的潜在药物靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b049/8961293/06bf7cd03e44/JEM_20211828_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b049/8961293/2a356cceb4d4/JEM_20211828_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b049/8961293/cb4e4625097d/JEM_20211828_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b049/8961293/6db59febb92f/JEM_20211828_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b049/8961293/1f9242675d35/JEM_20211828_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b049/8961293/a03f5e6f1139/JEM_20211828_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b049/8961293/87ff139fee96/JEM_20211828_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b049/8961293/5cdec0b125b1/JEM_20211828_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b049/8961293/5174e356f480/JEM_20211828_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b049/8961293/2f278eff4c80/JEM_20211828_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b049/8961293/a51c14847c80/JEM_20211828_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b049/8961293/d1370359c842/JEM_20211828_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b049/8961293/77cb2068b50a/JEM_20211828_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b049/8961293/a54921ccadcb/JEM_20211828_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b049/8961293/06bf7cd03e44/JEM_20211828_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b049/8961293/2a356cceb4d4/JEM_20211828_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b049/8961293/cb4e4625097d/JEM_20211828_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b049/8961293/6db59febb92f/JEM_20211828_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b049/8961293/1f9242675d35/JEM_20211828_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b049/8961293/a03f5e6f1139/JEM_20211828_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b049/8961293/87ff139fee96/JEM_20211828_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b049/8961293/5cdec0b125b1/JEM_20211828_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b049/8961293/5174e356f480/JEM_20211828_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b049/8961293/2f278eff4c80/JEM_20211828_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b049/8961293/a51c14847c80/JEM_20211828_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b049/8961293/d1370359c842/JEM_20211828_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b049/8961293/77cb2068b50a/JEM_20211828_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b049/8961293/a54921ccadcb/JEM_20211828_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b049/8961293/06bf7cd03e44/JEM_20211828_Fig9.jpg

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