MBL Binding with AhR Controls Th17 Immunity in Silicosis-Associated Lung Inflammation and Fibrosis.
MBL Binding with AhR Controls Th17 Immunity in Silicosis-Associated Lung Inflammation and Fibrosis.
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MBL 与 AhR 结合可控制矽肺相关肺部炎症和纤维化中的 Th17 免疫
DOI：
10.2147/jir.s357453
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发表时间：
2022
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
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甘露聚糖结合凝集素（MBL）是先天免疫系统的可溶性模式识别分子，主要在肝脏中合成并分泌到循环中。据报道，低血清MBL水平与肺部疾病的风险增加有关。在此，我们的目的是研究MBL在矽肺相关肺部炎症中的作用。检测矽肺患者血清MBL水平与Th 17免疫的相关性。进行体外研究以进一步证明MBL对Th 17极化的影响。在野生型（WT）或MBL缺陷型（MBL-/-）小鼠中，气管内注射二氧化硅以诱导硅肺相关的肺部炎症和纤维化。通过检测Th 17细胞反应，探讨MBL对矽肺的治疗作用。血清MBL水平高的矽肺患者显示肺功能改善。我们证明，血清MBL水平与矽肺患者的Th 17细胞频率呈负相关。MBL蛋白在Th 17或Treg极化条件下分别显著降低IL-17的表达，但增强Foxp 3在体外CD 4 + T细胞中的表达。Th 17细胞极化期间MBL的存在显着限制了芳烃受体（AhR）的表达，并抑制了信号转导和转录激活因子3（STAT 3）的磷酸化。用AhR拮抗剂处理可消除MBL对Th 17应答的影响。引人注目的是，MBL直接结合AhR并影响其核转位。此外，MBL-/-小鼠显示升高的Th 17细胞水平相比，野生型小鼠在响应二氧化硅的挑战。来自二氧化硅给药的MBL-/-小鼠的CD 4 + T淋巴细胞表现出比野生型对应物更多的AhR表达。我们的研究表明MBL通过控制AhR/STAT 3通路来限制Th 17免疫，从而为MBL缺乏患者的矽肺和其他炎性疾病提供了新的见解。
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.