Glucocorticoid-induced tumor necrosis factor receptor family-related protein exacerbates collagen-induced arthritis by enhancing the expansion of Th17 cells.
Rheumatoid arthritis (RA), a chronic autoimmune form of inflammatory joint disease, progressively affects multiple joints with pathological changes in the synovia, cartilage, and bone. Numerous studies have suggested a critical role for glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) in the pathogenesis of autoimmune arthritis by modulating both innate and adaptive immune reactions, but the underlying mechanisms by which GITR activation promotes arthritic progression remain largely unclear. In this study, we found that collagen-induced arthritis mice treated with the ligand of GITR (GITRL) displayed an earlier onset of arthritis with a markedly increased severity of arthritic symptoms and joint damage, in which significantly increased Th17 cells in both spleen and draining lymph nodes were observed. Notably, results showed that a marked expansion of Th17 cells with increased RORγt mRNA expression was induced from naïve CD4(+) T cells when cultured with GITRL. Consistently, normal mice that were treated with GITRL were found to display a substantial expansion of splenic Th17 cells. Furthermore, we detected elevated serum levels of GITRL in patients with RA, which were positively correlated with an increase in interleukin-17 production. Taken together, the results from this study have revealed a new function of GITRL in exacerbating autoimmune arthritis via the enhancement of the expansion of Th17 cells.
Department of Laboratory Medicine, The Affiliated People's Hospital and School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China. Electronic address: sjwjs@ujs.edu.cn.
Shengjun
S
Wang
Department of Laboratory Medicine, The Affiliated People's Hospital and School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, China.
Ye
Y
Shi
Department of Pathology and Centre of Infection and Immunology, The University of Hong Kong, Hong Kong, China.
Min
M
Yang
Department of Laboratory Medicine, The Affiliated People's Hospital and School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, China.
Jie
J
Ma
Department of Laboratory Medicine, The Affiliated People's Hospital and School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, China.
Jie
J
Tian
Department of Laboratory Medicine, The Affiliated People's Hospital and School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, China.
Jianguo
J
Chen
Zhenjiang Key Laboratory of Medical Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
Chaoming
C
Mao
Zhenjiang Key Laboratory of Medical Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
Zhijun
Z
Jiao
Department of Pathology and Centre of Infection and Immunology, The University of Hong Kong, Hong Kong, China.
King-Hung
KH
Ko
Department of Laboratory Medicine, The Affiliated People's Hospital and School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, China.
Samuel Essien
SE
Baidoo
Department of Laboratory Medicine, The Affiliated People's Hospital and School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, China.
Huaxi
H
Xu
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
Zichun
Z
Hua
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China; Department of Pathology and Centre of Infection and Immunology, The University of Hong Kong, Hong Kong, China. Electronic address: liweilu@hkucc.hku.hk.
Liwei
L
Lu
D000818:Animals; D001169:Arthritis, Experimental / Q000209:etiology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002454:Cell Differentiation; D002455:Cell Division / Q000502:physiology; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D008024:Ligands; D008198:Lymph Nodes / Q000473:pathology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D011994:Recombinant Proteins; D013154:Spleen / Q000473:pathology; D058504:Th17 Cells / Q000378:metabolism / Q000473:pathology*
D053450:Glucocorticoid-Induced TNFR-Related Protein; D020381:Interleukin-17; D008024:Ligands; D011994:Recombinant Proteins