Osteopontin Links Myeloid Activation and Disease Progression in Systemic Sclerosis.
Osteopontin Links Myeloid Activation and Disease Progression in Systemic Sclerosis.
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DOI：
10.1016/j.xcrm.2020.100140
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发表时间：
2020-11-17
期刊：
影响因子：
--
通讯作者：
Ramalingam TR
中科院分区：
文献类型：
--
作者：
Gao X;Jia G;Guttman A;DePianto DJ;Morshead KB;Sun KH;Ramamoorthi N;Vander Heiden JA;Modrusan Z;Wolters PJ;Jahreis A;Arron JR;Khanna D;Ramalingam TR
进行性肺纤维化是系统性硬化症（SSc）患者死亡的主要原因，但其潜在机制仍不清楚。我们证明，免疫复合物 (IC) 部分通过骨桥蛋白 (OPN) 分泌激活人单核细胞，促进肺成纤维细胞迁移，而自分泌单核细胞集落刺激因子 (MCSF) 和白细胞介素 6 (IL-6) 活性会放大骨桥蛋白 (OPN) 的分泌。大量和单细胞 RNA 测序表明，SSc 肺组织中 OPN 表达升高在巨噬细胞中富集，与 CCL18 表达部分重叠。患有间质性肺疾病 (ILD) 的 SSc 患者血清 OPN 升高，预示着 SSc 人群未来肺功能恶化。托珠单抗（单克隆抗 IL-6 受体）治疗后血清 OPN 水平下降，证实了 SSc 患者中 IL-6 和 OPN 之间的联系。总的来说，这些数据表明自身抗体与肺纤维化进展之间似乎存在联系，其中循环 OPN 作为 IC 驱动的促纤维化巨噬细胞活性的系统代表，突显了其作为 SSc ILD 的有前途的生物标志物的潜力。免疫复合物通过 MCSF 和 IL-6 诱导巨噬细胞分泌骨桥蛋白 (OPN)，在纤维化间质性肺疾病中，OPN 主要由巨噬细胞表达。循环 OPN 水平升高，可预测系统性硬化症的疾病进展。IL-6 受体阻断可降低系统性硬化症患者的循环 OPN 水平。显示免疫复合物通过 IL-6 和 MCSF 诱导巨噬细胞/单核细胞中骨桥蛋白的表达。骨桥蛋白由纤维化肺组织中的巨噬细胞表达。血清骨桥蛋白水平可预测系统性硬化症患者的纤维化进展，并且在 IL-6 受体阻断后降低，突显其作为生物标志物的潜力。
Progressive lung fibrosis is a major cause of mortality in systemic sclerosis (SSc) patients, but the underlying mechanisms remain unclear. We demonstrate that immune complexes (ICs) activate human monocytes to promote lung fibroblast migration partly via osteopontin (OPN) secretion, which is amplified by autocrine monocyte colony stimulating factor (MCSF) and interleukin-6 (IL-6) activity. Bulk and single-cell RNA sequencing demonstrate that elevated OPN expression in SSc lung tissue is enriched in macrophages, partially overlapping with CCL18 expression. Serum OPN is elevated in SSc patients with interstitial lung disease (ILD) and prognosticates future lung function deterioration in SSc cohorts. Serum OPN levels decrease following tocilizumab (monoclonal anti-IL-6 receptor) treatment, confirming the connection between IL-6 and OPN in SSc patients. Collectively, these data suggest a plausible link between autoantibodies and lung fibrosis progression, where circulating OPN serves as a systemic proxy for IC-driven profibrotic macrophage activity, highlighting its potential as a promising biomarker in SSc ILD. Immune complexes induce osteopontin (OPN) secretion from macrophages via MCSF and IL-6 OPN is expressed predominantly by macrophages in fibrotic interstitial lung disease Circulating OPN levels are elevated and predict disease progression in systemic sclerosis IL-6 receptor blockade reduces levels of circulating OPN in systemic sclerosis patients Gao et al. show that immune complexes induce expression of osteopontin in macrophages/monocytes via IL-6 and MCSF. Osteopontin is expressed by macrophages in fibrotic lung tissue. Serum osteopontin levels predict fibrosis progression in systemic sclerosis patients and is decreased following IL-6 receptor blockade, highlighting its potential as a biomarker.
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DOI：
10.1183/13993003.02441-2018
发表时间：
2019-08
期刊：
The European respiratory journal
影响因子：
--
作者：
Morse C;Tabib T;Sembrat J;Buschur KL;Bittar HT;Valenzi E;Jiang Y;Kass DJ;Gibson K;Chen W;Mora A;Benos PV;Rojas M;Lafyatis R
通讯作者：
Lafyatis R
影响因子：
33.7
作者：
Nihtyanova, Svetlana I.;Denton, Christopher P.
通讯作者：
Denton, Christopher P.
影响因子：
13.3
作者：
Khanna, Dinesh;Berrocal, Veronica J.;Furst, Daniel E.
通讯作者：
Furst, Daniel E.
DOI：
10.1038/nri3073
发表时间：
2011-10-14
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
15.9
作者：
Duffield, JS;Forbes, SJ;Iredale, JP
通讯作者：
Iredale, JP