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

Yunzhi Liu,1,2,* Na Zhao,3,* Qishan Xu,1,2 Fan Deng,1 Ping Wang,1,2 Lijun Dong,1,2 Xiao Lu,2 Lihua Xia,3 Mingyong Wang,4 Zhengliang Chen,2 Jia Zhou,2 Daming Zuo1,5 1Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China; 2Guangdong Province Key Laboratory of Proteomics, Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China; 3Department of Medical Laboratory, Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou, Guangdong, 510399, People’s Republic of China; 4Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang, 453003, People’s Republic of China; 5Microbiome Medicine Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510282, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jia Zhou, 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, Tel +86-20-61648220, Fax +86-20-61648221, Email yuguomm@smu.edu.cn Daming Zuo, Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China, Tel +86-20-61648552, Fax + 86-20-61648221, Email zdaming@smu.edu.cnObjective: 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: silicosis, mannan-binding lectin, aryl hydrocarbon receptor, signal transducer and activator of transcription 3, Th17 cell