Liu Yunzhi, Zhao Na, Xu Qishan, Deng Fan, Wang Ping, Dong Lijun, Lu Xiao, Xia Lihua, Wang Mingyong, Chen Zhengliang, Zhou Jia, Zuo Daming
Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, 510515, People's Republic of China.
Guangdong Province Key Laboratory of Proteomics, Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, People's Republic of China.
J Inflamm Res. 2022 Jul 28;15:4315-4329. doi: 10.2147/JIR.S357453. eCollection 2022.
Mannan-binding lectin (MBL), a soluble pattern recognition molecule of the innate immune system, is primarily synthesized in the liver and secreted into the circulation. Low serum level of MBL has been reported to be related to an increased risk of lung diseases. Herein, we aimed to investigate the function of MBL in silicosis-associated pulmonary inflammation.
Serum collected from silicosis patients was tested for correlation between serum MBL levels and Th17 immunity. In vitro studies were performed to further demonstrated the effect of MBL on Th17 polarization. Silica was intratracheally injected in wild type (WT) or MBL-deficient (MBL) mice to induce silicosis-associated lung inflammation and fibrosis. Th17 response was evaluated to explore the effect of MBL on silicosis in vivo.
Silicosis patients with high serum MBL levels displayed ameliorative lung function. We demonstrated that serum MBL levels negatively correlated to Th17 cell frequency in silicosis patients. MBL protein markedly reduced expression of IL-17 but enhanced expression of Foxp3 in CD4 T cells in vitro when subjected to Th17 or Treg polarizing conditions, respectively. The presence of MBL during Th17 cell polarization significantly limited aryl hydrocarbon receptor (AhR) expression and suppressed the signal transducer and activator of transcription 3 (STAT3) phosphorylation. Treatment with the AhR antagonist abolished the effect of MBL on Th17 response. Strikingly, MBL directly bound to AhR and affected its nuclear translocation. Furthermore, MBL mice displayed elevated Th17 cell levels compared with WT mice in response to the silica challenge. The CD4 T lymphocytes from silica-administrated MBL mice exhibited more AhR expression than the wild-type counterparts.
Our study suggested that MBL limited the Th17 immunity via controlling the AhR/STAT3 pathway, thus providing new insight into silicosis and other inflammatory diseases in patients with MBL deficiency.
甘露聚糖结合凝集素（MBL）是先天性免疫系统的一种可溶性模式识别分子，主要在肝脏合成并分泌入血液循环。据报道，血清MBL水平低与肺部疾病风险增加有关。在此，我们旨在研究MBL在矽肺相关肺部炎症中的作用。
检测矽肺患者血清中MBL水平与Th17免疫之间的相关性。进行体外研究以进一步证明MBL对Th17极化的影响。将二氧化硅经气管内注射到野生型（WT）或MBL缺陷型（MBL-/-）小鼠中，以诱导矽肺相关的肺部炎症和纤维化。评估Th17反应以探讨MBL在体内对矽肺的影响。
血清MBL水平高的矽肺患者肺功能改善。我们证明矽肺患者血清MBL水平与Th17细胞频率呈负相关。在分别处于Th17或Treg极化条件下时，MBL蛋白在体外可显著降低CD4+ T细胞中IL-17的表达，但增强Foxp3的表达。在Th17细胞极化过程中MBL的存在显著限制芳烃受体（AhR）的表达并抑制信号转导子和转录激活子3（STAT3）的磷酸化。用AhR拮抗剂处理可消除MBL对Th17反应的影响。令人惊讶的是，MBL直接与AhR结合并影响其核转位。此外，与WT小鼠相比，MBL-/-小鼠在受到二氧化硅攻击后Th17细胞水平升高。来自接受二氧化硅处理的MBL-/-小鼠的CD4+ T淋巴细胞比野生型对应物表现出更多的AhR表达。
我们的研究表明，MBL通过控制AhR/STAT3途径限制Th17免疫，从而为MBL缺乏患者的矽肺和其他炎症性疾病提供了新的见解。
