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MBL Binding with AhR Controls Th17 Immunity in Silicosis-Associated Lung Inflammation and Fibrosis
Yunzhi Liu1,2, Na Zhao3, Qishan Xu1,2
1Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, 510515, People's Republic of China.
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 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.
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.
Insights
Mannan-binding lectin (MBL) limits Th17 immunity in silicosis by inhibiting the aryl hydrocarbon receptor (AhR)/STAT3 pathway. This finding offers new insights into MBL deficiency and inflammatory lung diseases.
Area of Science:
- Immunology
- Innate Immunity
- Pulmonary Inflammation
Background:
- Mannan-binding lectin (MBL) is a key pattern recognition molecule in innate immunity.
- Low MBL serum levels are linked to increased risk of lung diseases, including silicosis.
- The specific role of MBL in silicosis-associated pulmonary inflammation requires further investigation.
Purpose of the Study:
- To investigate the function of MBL in silicosis-associated pulmonary inflammation.
- To explore the correlation between serum MBL levels and Th17 immunity in silicosis patients.
- To elucidate the mechanism by which MBL influences Th17 polarization in silicosis.
Main Methods:
- Serum MBL levels and Th17 cell frequency were analyzed in silicosis patients.
- In vitro studies assessed MBL's effect on Th17 and Treg polarization of CD4+ T cells.
- Silicosis was induced in wild-type and MBL-deficient mice via intratracheal silica injection.
Main Results:
- Higher serum MBL levels correlated with improved lung function and lower Th17 cell frequency in silicosis patients.
- MBL suppressed IL-17 expression and promoted Foxp3 expression in CD4+ T cells.
- MBL inhibited aryl hydrocarbon receptor (AhR) expression and STAT3 phosphorylation during Th17 polarization, directly binding to AhR.
- MBL-deficient mice exhibited increased Th17 cell levels and AhR expression post-silica challenge.
Conclusions:
- MBL limits Th17 immunity in silicosis by modulating the AhR/STAT3 pathway.
- MBL plays a protective role in silicosis by controlling excessive Th17 responses.
- These findings provide novel insights into silicosis pathogenesis and potential therapeutic strategies for MBL-deficient individuals with inflammatory diseases.
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