Aberrantly Expressed Galectin-9 Is Involved in the Immunopathogenesis of Anti-MDA5-Positive Dermatomyositis-Associated Interstitial Lung Disease.
Aberrantly Expressed Galectin-9 Is Involved in the Immunopathogenesis of Anti-MDA5-Positive Dermatomyositis-Associated Interstitial Lung Disease.
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DOI：
10.3389/fcell.2021.628128
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发表时间：
2021
影响因子：
5.5
通讯作者：
Peng QL
中科院分区：
文献类型：
--
作者：
Liang L;Zhang YM;Shen YW;Song AP;Li WL;Ye LF;Lu X;Wang GC;Peng QL
皮肌炎（DM）相关的快速进展性间质性肺疾病（RP-ILD）死亡率高，预后差。半乳糖凝集素-9（Galectin-9，Gal-9）在免疫调节中具有多种功能。我们研究了Gal-9在DM患者中的表达及其与DM-ILD的相关性。共有154名特发性炎性肌病患者和30名健康对照者参加了这项研究。采用横断面和纵向研究分析血清Gal-9水平与临床特征之间的关系。采用酶联免疫吸附试验和qRT-PCR检测DM患者血清和外周血单个核细胞（PBMCs）中Gal-9的表达。采用免疫组化方法分析抗黑色素瘤分化相关基因5（MDA5）阳性患者肺组织中Gal-9及其配体（T细胞免疫球蛋白粘蛋白（Tim）-3和CD44）的表达。在体外研究了Gal-9对人肺成纤维细胞（MRC-5）的作用。DM患者的血清Gal-9水平显著高于免疫介导的坏死性肌病患者和健康对照（所有p <0.001）。在抗-MDA5阳性DM患者中观察到比抗-MDA5阴性DM患者更高的血清Gal-9水平[33.8（21.9 - 44.7）对16.2（10.0 - 26.9）ng/mL，p <0.001]。在抗MDA5阳性的DM患者中，血清Gal-9水平与RP-ILD严重程度相关。在横断面和纵向研究中，血清Gal-9水平与抗MDA5阳性DM患者的疾病活动性显著相关。从抗MDA 5阳性DM患者分离的PBMC（3.7 ± 2.3 ng/mL）产生的Gal-9水平高于免疫介导的坏死性肌病患者（1.1 ± 0.3 ng/mL，p = 0.022）和健康对照（1.4 ± 1.2 ng/mL，p = 0.045）。抗-MDA5阳性DM患者PBMC中Gal-9 mRNA水平与I型干扰素诱导基因MX1（r = 0.659，p = 0.020）和IFIH 1（r = 0.787，p = 0.002）水平呈正相关。免疫组化显示DM和RP-ILD患者肺组织中Gal-9和Tim-3表达增加。在体外刺激与Gal-9蛋白增加CCL2 mRNA的表达在MRC-5成纤维细胞。在抗MDA5阳性的DM患者中，Gal-9可能是监测疾病活动性的有前景的生物标志物，特别是RP-ILD严重程度。Gal-9/Tim-3轴的异常表达可能参与DM-ILD的免疫发病机制。
Dermatomyositis (DM) associated rapidly progressive interstitial lung disease (RP-ILD) has high mortality rate and poor prognosis. Galectin-9 (Gal-9) plays multiple functions in immune regulation. We investigated Gal-9 expression in DM patients and its association with DM-ILD. A total of 154 idiopathic inflammatory myopathy patients and 30 healthy controls were enrolled in the study. Cross-sectional and longitudinal studies were used to analyze the association between serum Gal-9 levels and clinical features. Enzyme-linked immunosorbent assay and qRT-PCR were used to examine Gal-9 expression in the sera and isolated peripheral blood mononuclear cells (PBMCs) from DM patients. Immunohistochemistry was performed to analyze the expression of Gal-9 and its ligand (T-cell immunoglobulin mucin (Tim)-3 and CD44) in lung tissues from anti-melanoma differentiation-associated gene 5 (MDA5)-positive patients. The effect of Gal-9 on human lung fibroblasts (MRC-5) was investigated in vitro. Serum Gal-9 levels were significantly higher in DM patients than in immune-mediated necrotizing myopathy patients and healthy controls (all p < 0.001). Higher serum Gal-9 levels were observed in anti-MDA5-positive DM patients than in anti-MDA5-negative DM patients [33.8 (21.9–44.7) vs. 16.2 (10.0–26.9) ng/mL, p < 0.001]. Among the anti-MDA5-positive DM patients, serum Gal-9 levels were associated with RP-ILD severity. Serum Gal-9 levels were significantly correlated with disease activity in anti-MDA5-positive DM patients in both cross-sectional and longitudinal studies. PBMCs isolated from anti-MDA5-positive DM patients (3.7 ± 2.3 ng/mL) produced higher levels of Gal-9 than those from immune-mediated necrotizing myopathy patients (1.1 ± 0.3 ng/mL, p = 0.022) and healthy controls (1.4 ± 1.2 ng/mL, p = 0.045). The mRNA levels of Gal-9 were positively correlated with the levels of type-I interferon-inducible genes MX1 (r = 0.659, p = 0.020) and IFIH1 (r = 0.787, p = 0.002) in PBMCs from anti-MDA5-positive DM patients. Immunohistochemistry revealed increased Gal-9 and Tim-3 expression in the lung tissues of patients with DM and RP-ILD. In vitro stimulation with Gal-9 protein increased CCL2 mRNA expression in MRC-5 fibroblasts. Among anti-MDA5-positive DM patients, Gal-9 could be a promising biomarker for monitoring disease activity, particularly for RP-ILD severity. Aberrant expression of the Gal-9/Tim-3 axis may be involved in the immunopathogenesis of DM-ILD.
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