한빛사 논문
Jin-Sun Kong1,2,a, Ji-Hwan Park3,4,a, Seung-Ah Yoo1, Ki-Myo Kim1, Yeung-Jin Bae1, Yune-Jung Park1,5, Chul-Soo Cho1,5, Daehee Hwang3,6,b, and Wan-Uk Kim1,2,5,b
1Center for Integrative Rheumatoid Transcriptomics and Dynamics, The Catholic University of Korea, Seoul 06591, Republic of Korea
2Department of Biomedicine & Health Sciences, The Catholic University of Korea, Seoul 06591, Republic of Korea
3Center for Plant Aging Research, Institute for Basic Science (IBS), Daegu 42988, Republic of Korea
4Korean Bioinformation Center, Korea Research Institute of Bioscience & Biotechnology, Daejeon 34141, Republic of Korea
5Division of Rheumatology, Department of Internal Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
6Department of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea
aThese authors contributed equally to this work.
bTo whom correspondence should be addressed.
Abstract
Despite recent advances in understanding chronic inflammation remission, global analyses have not been explored to systematically discover genes or pathways underlying the resolution dynamics of chronic inflammatory diseases. Here, we performed time-course gene expression profiling of mouse synovial tissues along progression and resolution of collagen-induced arthritis (CIA) and identified genes associated with inflammation resolution. Through network analysis of these genes, we predicted three key secretory factors responsible for the resolution of CIA: Itgb1, Rps3, and Ywhaz. These factors were predominantly expressed by regulatory T cells and anti-inflammatory M2 macrophages, suppressing production of pro-inflammatory cytokines. In particular, Ywhaz was elevated in the sera of mice with arthritis resolution and in the urine of rheumatoid arthritis (RA) patients with good therapeutic responses. Moreover, adenovirus-mediated transfer of the Ywhaz gene to the affected joints substantially inhibited arthritis progression in mice with CIA and suppressed expression of pro-inflammatory cytokines in joint tissues, lymph nodes, and spleens, suggesting Ywhaz as an excellent target for RA therapy. Therefore, our comprehensive analysis of dynamic synovial transcriptomes provides previously unidentified anti-arthritic genes, Itgb1, Rps3, and Ywhaz, which can serve as molecular markers to predict disease remission, as well as therapeutic targets for chronic inflammatory arthritis.
Key Words: Rheumatoid arthritis, Transcriptomes, Resolution dynamics, Pro-resolving genes
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