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溴结构域抑制剂调节 FcγR 介导的单核吞噬细胞激活和趋化性。

Bromodomain Inhibitors Modulate FcγR-Mediated Mononuclear Phagocyte Activation and Chemotaxis.

机构信息

Molecular Immunity Unit, Department of Medicine, Medical Research Council Laboratory of Molecular Biology, University of Cambridge, Cambridge, United Kingdom.

Cellular Genetics, Wellcome Sanger Institute, Cambridge, United Kingdom.

出版信息

Front Immunol. 2022 May 10;13:885101. doi: 10.3389/fimmu.2022.885101. eCollection 2022.

DOI:10.3389/fimmu.2022.885101
PMID:35619690
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9127238/
Abstract

IgG antibodies form immune complexes (IC) that propagate inflammation and tissue damage in autoimmune diseases such as systemic lupus erythematosus. IgG IC engage Fcγ receptors (FcγR) on mononuclear phagocytes (MNP), leading to widespread changes in gene expression that mediate antibody effector function. Bromodomain and extra-terminal domain (BET) proteins are involved in governing gene transcription. We investigated the capacity of BET protein inhibitors (iBET) to alter IgG FcγR-mediated MNP activation. We found that iBET dampened IgG IC-induced pro-inflammatory gene expression and decreased activating FcγR expression on MNPs, reducing their ability to respond to IgG IC. Despite FcγR downregulation, iBET-treated macrophages demonstrated increased phagocytosis of protein antigen, IgG IC, and apoptotic cells. iBET also altered cell morphology, generating more amoeboid MNPs with reduced adhesion. iBET treatment impaired chemotaxis towards a CCL19 gradient in IC-stimulated dendritic cells (DC) , and inhibited IC-induced DC migration to draining lymph nodes , in a DC-intrinsic manner. Altogether, our data show that iBET modulates FcγR-mediated MNP activation and migration, revealing the therapeutic potential of BET protein inhibition in antibody-mediated diseases.

摘要

IgG 抗体形成免疫复合物（IC），在自身免疫性疾病（如系统性红斑狼疮）中引发炎症和组织损伤。IgG IC 与单核吞噬细胞（MNP）上的 Fcγ 受体（FcγR）结合，导致介导抗体效应功能的基因表达广泛改变。溴结构域和末端结构域（BET）蛋白参与调节基因转录。我们研究了 BET 蛋白抑制剂（iBET）改变 IgG FcγR 介导的 MNP 激活的能力。我们发现 iBET 抑制了 IgG IC 诱导的促炎基因表达，并降低了 MNPs 上激活的 FcγR 表达，从而降低了它们对 IgG IC 的反应能力。尽管 FcγR 下调，但 iBET 处理的巨噬细胞表现出对蛋白抗原、IgG IC 和凋亡细胞的吞噬作用增加。iBET 还改变了细胞形态，产生了具有降低黏附性的更多阿米巴样 MNP。iBET 处理还损害了 IC 刺激的树突状细胞（DC）中趋化因子向 CCL19 梯度的迁移，并以 DC 内在的方式抑制了 IC 诱导的 DC 向引流淋巴结的迁移。总之，我们的数据表明，iBET 调节了 FcγR 介导的 MNP 激活和迁移，揭示了 BET 蛋白抑制在抗体介导的疾病中的治疗潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f64/9127238/699e012bf5b8/fimmu-13-885101-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f64/9127238/a586ba8caf99/fimmu-13-885101-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f64/9127238/38f3b18e2ddf/fimmu-13-885101-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f64/9127238/83df774e3391/fimmu-13-885101-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f64/9127238/ca2c2b8075ed/fimmu-13-885101-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f64/9127238/2874617f32ae/fimmu-13-885101-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f64/9127238/699e012bf5b8/fimmu-13-885101-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f64/9127238/a586ba8caf99/fimmu-13-885101-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f64/9127238/38f3b18e2ddf/fimmu-13-885101-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f64/9127238/83df774e3391/fimmu-13-885101-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f64/9127238/ca2c2b8075ed/fimmu-13-885101-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f64/9127238/2874617f32ae/fimmu-13-885101-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f64/9127238/699e012bf5b8/fimmu-13-885101-g006.jpg

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