4.6 Article

MBL Binding with AhR Controls Th17 Immunity in Silicosis-Associated Lung Inflammation and Fibrosis

期刊

JOURNAL OF INFLAMMATION RESEARCH
卷 15, 期 -, 页码 4315-4329

出版社

DOVE MEDICAL PRESS LTD
DOI: 10.2147/JIR.S357453Journalof

关键词

silicosis; mannan-binding lectin; aryl hydrocarbon receptor; signal transducer and activator of transcription 3; Th17 cell

资金

  1. National Natural Science Foundation of China [82071781, 81971550, 81873872, 81903269]
  2. Science and Technology Planning Project of Guangzhou [202002030160, 202102080005]
  3. Innovation team of chronic kidney disease with integrated traditional Chinese and Western Medicine [2019KCXTD014]
  4. Natural Science Foundation of Guangdong [:2021A1515011546, 2021A1515010081, 2021A1515012205]
  5. Guangdong Provincial Key Laboratory of Occupational Disease Prevention and Treatment [:2017B030314152]

向作者/读者索取更多资源

This study found that MBL limits Th17 immunity in silicosis patients by controlling the AhR/STAT3 pathway, providing new insight into the role of MBL deficiency in silicosis and other inflammatory diseases.
Objective: 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. Methods: 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. Results: 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 T-reg 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. Conclusion: 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.

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