CXCR4+ 1 型先天性淋巴细胞的募集使肉样瘤病与其他皮肤肉芽肿疾病区分开来。

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Satish Sati, Jianhe Huang, Anna E Kersh, Parker Jones, Olivia Ahart, Christina Murphy, Stephen M Prouty, Matthew L Hedberg, Vaibhav Jain, Simon G Gregory, Denis H Leung, John T Seykora, Misha Rosenbach, Thomas H Leung
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引用次数: 0

摘要

肉样瘤病是一种多器官肉芽肿性疾病,缺乏诊断生物标志物和靶向治疗。利用肉样瘤和非肉样瘤皮肤肉芽肿患者的血液和皮肤,我们发现不同疾病的皮肤肉芽肿表现出独特的免疫细胞招募和分子特征。肉样瘤皮肤肉芽肿特异性地富集了1型先天性淋巴细胞(ILC1s)和B细胞,并表现出与成熟的三级淋巴结构(TLSs)形成相关的分子程序,包括CXCL12/CXCR4信号的增加。肺肉样瘤病肉芽肿也表现出类似的免疫细胞招募。因此,肉芽肿的形成并不是一般的分子反应。除了组织特异性效应外,肉样瘤病患者的循环 ILC1s 也增加了 8 倍,这与治疗状态有关。在肉样瘤病中,多种免疫细胞类型诱导了 CXCL12/CXCR4 信号,包括 Th1 T 细胞、巨噬细胞和 ILCs。从机理上讲,抑制 CXCR4 可减少肉样瘤病激活的免疫细胞迁移,在非感染性小鼠模型中,靶向 CXCR4 或全部 ILCs 可减轻肉芽肿的形成。总之,我们的研究结果表明,ILC1 是一种组织和循环生物标志物,可将肉样瘤病与其他皮肤肉芽肿疾病区分开来。重新利用现有的 CXCR4 抑制剂可能会为这种毁灭性疾病提供一种新的靶向治疗方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Recruitment of CXCR4+ type 1 innate lymphoid cells distinguishes sarcoidosis from other skin granulomatous diseases.

Sarcoidosis is a multiorgan granulomatous disease that lacks diagnostic biomarkers and targeted treatments. Using blood and skin from patients with sarcoid and non-sarcoid skin granulomas, we discovered that skin granulomas from different diseases exhibit unique immune cell recruitment and molecular signatures. Sarcoid skin granulomas were specifically enriched for type 1 innate lymphoid cells (ILC1s) and B cells and exhibited molecular programs associated with formation of mature tertiary lymphoid structures (TLSs), including increased CXCL12/CXCR4 signaling. Lung sarcoidosis granulomas also displayed similar immune cell recruitment. Thus, granuloma formation was not a generic molecular response. In addition to tissue-specific effects, patients with sarcoidosis exhibited an 8-fold increase in circulating ILC1s, which correlated with treatment status. Multiple immune cell types induced CXCL12/CXCR4 signaling in sarcoidosis, including Th1 T cells, macrophages, and ILCs. Mechanistically, CXCR4 inhibition reduced sarcoidosis-activated immune cell migration, and targeting CXCR4 or total ILCs attenuated granuloma formation in a noninfectious mouse model. Taken together, our results show that ILC1s are a tissue and circulating biomarker that distinguishes sarcoidosis from other skin granulomatous diseases. Repurposing existing CXCR4 inhibitors may offer a new targeted treatment for this devastating disease.

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来源期刊
Journal of Clinical Investigation
Journal of Clinical Investigation 医学-医学:研究与实验
CiteScore
24.50
自引率
1.30%
发文量
1034
审稿时长
2 months
期刊介绍: The Journal of Clinical Investigation, established in 1924 by the ASCI, is a prestigious publication that focuses on breakthroughs in basic and clinical biomedical science, with the goal of advancing the field of medicine. With an impressive Impact Factor of 15.9 in 2022, it is recognized as one of the leading journals in the "Medicine, Research & Experimental" category of the Web of Science. The journal attracts a diverse readership from various medical disciplines and sectors. It publishes a wide range of research articles encompassing all biomedical specialties, including Autoimmunity, Gastroenterology, Immunology, Metabolism, Nephrology, Neuroscience, Oncology, Pulmonology, Vascular Biology, and many others. The Editorial Board consists of esteemed academic editors who possess extensive expertise in their respective fields. They are actively involved in research, ensuring the journal's high standards of publication and scientific rigor.
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