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

Yunzhi Liu; Na Zhao; Qishan Xu; Fan Deng; Ping Wang; Lijun Dong; Xiao Lu; Lihua Xia; Mingyong Wang; Zhengliang Chen; Jia Zhou; Daming Zuo

doi:10.2147/JIR.S357453

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

J Inflamm Res. 2022 Jul 28:15:4315-4329. doi: 10.2147/JIR.S357453. eCollection 2022.

Authors

Yunzhi Liu^#^{1

2}, Na Zhao^#³, Qishan Xu^{1

2}, Fan Deng¹, Ping Wang^{1

2}, Lijun Dong^{1

2}, Xiao Lu², Lihua Xia³, Mingyong Wang⁴, Zhengliang Chen², Jia Zhou², Daming Zuo^{1

5}

Affiliations

¹ Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, 510515, People's Republic of China.
² 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.
³ Department of Medical Laboratory, Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou, Guangdong, 510399, People's Republic of China.
⁴ Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang, 453003, People's Republic of China.
⁵ Microbiome Medicine Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510282, People's Republic of China.

^# Contributed equally.

Abstract

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.

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

Grants and funding

This work was supported in part by the National Natural Science Foundation of China (grant no.: 82071781, 81971550, 81873872, and 81903269), Science and Technology Planning Project of Guangzhou (grant no.: 202002030160 and 202102080005), Innovation team of chronic kidney disease with integrated traditional Chinese and Western Medicine (grant no.: 2019KCXTD014), Natural Science Foundation of Guangdong (grant no.:2021A1515011546, 2021A1515010081, 2021A1515012205) and Guangdong Provincial Key Laboratory of Occupational Disease Prevention and Treatment (grant no.:2017B030314152).