Involvement of TLR7 MyD88-dependent signaling pathway in the pathogenesis of adult-onset Still's disease
- Equal contributors
1 Faculty of Medicine, National Yang-Ming University, No. 155, Sec. 2, Li-Nong Street, Taipei 112, Taiwan
2 Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, No. 160, Section 3, Taichung-Kang Road, Taichung, 407, Taiwan
3 Infection and Immunity Research Center, National Yang-Ming University, No. 155, Sec. 2, Li-Nong Street, Taipei 112, Taiwan
4 Institute of Microbiology and Immunology, Chung-Shan Medical University, No.110, Sec.1, Jianguo N.Rd., Taichung, 402, Taiwan
5 Institute of Biomedical Science, National Chung-Hsing University, No.250, Kuo-Kuang Rd., Taichung, 402, Taiwan
6 Division of Immunology and Rheumatology, China Medical University Hospital, No. 2, Yu-De Rd., Taichung, 404, Taiwan
Arthritis Research & Therapy 2013, 15:R39 doi:10.1186/ar4193Published: 4 March 2013
The objective of this study was to investigate the potential role of the Toll-like receptor 7 (TLR7) signaling pathway in the pathogenesis of adult-onset Still's disease (AOSD).
Frequencies of TLR7-expressing precursor of myeloid dendritic cells (pre-mDCs) and mDCs in 28 AOSD patients, 28 patients with systemic lupus erythematosus (SLE) and 12 healthy controls (HC) were determined by flow cytometry analysis. Transcript and protein levels of TLR7 signaling molecules in peripheral blood mononuclear cells (PBMCs) were evaluated by quantitative PCR and western blotting respectively. Serum cytokines levels were measured by ELISA.
Significantly higher median frequencies of TLR7-expressing pre-mDCs and mDCs were observed in AOSD patients (65.5% and 14.9%, respectively) and in SLE patients (60.3% and 14.4%, respectively) than in HC (42.8% and 8.8%, respectively; both P <0.001). Transcript and protein levels of TLR7-signaling molecules, including MyD88, TRAF6, IRAK4 and IFN-α, were upregulated in AOSD patients and SLE patients compared with those in HC. Disease activity scores were positively correlated with the frequencies of TLR7-expressing mDCs and expression levels of TLR7 signaling molecules in both AOSD and SLE patients. TLR7 ligand (imiquimod) stimulation of PBMCs resulted in significantly enhanced levels of interleukin (IL)-1β, IL-6, IL-18 and IFN-α in AOSD and SLE patients. Frequencies of TLR7-expressing mDCs and expression levels of TLR7 signaling molecules significantly decreased after effective therapy.
Elevated levels of TLR7 signaling molecules and their positive correlation with disease activity in AOSD patients suggest involvement of the TLR7 signaling pathway in the pathogenesis of this disease. The overexpression of TLR7 MyD88-dependent signaling molecules may be a common pathogenic mechanism for both AOSD and SLE.