Dynamic transcriptome analysis unveils key proresolving factors of chronic inflammatory arthritis
Jin-Sun Kong, … , Daehee Hwang, Wan-Uk Kim
Jin-Sun Kong, … , Daehee Hwang, Wan-Uk Kim
Published May 14, 2020
Citation Information: J Clin Invest. 2020;130(8):3974-3986. https://doi.org/10.1172/JCI126866.
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Research Article Autoimmunity Inflammation

Dynamic transcriptome analysis unveils key proresolving factors of chronic inflammatory arthritis

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 3 key secretory factors responsible for the resolution of CIA: Itgb1, Rps3, and Ywhaz. These factors were predominantly expressed by Tregs and antiinflammatory M2 macrophages, suppressing production of proinflammatory 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 proinflammatory cytokines in joint tissues, lymph nodes, and spleens, suggesting Ywhaz is an excellent target for RA therapy. Therefore, our comprehensive analysis of dynamic synovial transcriptomes provides previously unidentified antiarthritic genes, Itgb1, Rps3, and Ywhaz, which can serve as molecular markers to predict disease remission, as well as therapeutic targets for chronic inflammatory arthritis.

Authors

Jin-Sun Kong, Ji-Hwan Park, Seung-Ah Yoo, Ki-Myo Kim, Yeung-Jin Bae, Yune-Jung Park, Chul-Soo Cho, Daehee Hwang, Wan-Uk Kim

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Figure 8

Ad-Ywhaz inhibition of CIA in mice.

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Ad-Ywhaz inhibition of CIA in mice. (A) Arthritis severity measured at 2...
(A) Arthritis severity measured at 2- or 3-day intervals up to 52 days after the primary immunization with type II collagen. Intra-articular injection of 1 × 108 PFU of Ad-Ywhaz or Ad-Con at 30 and 37 days are indicated by arrows (n = 8 per group and per time point). Data are representative of 2 independent experiments with similar results. (B) Ad-Ywhaz suppression of foot swelling (left, top) and chronic inflammation in the ankle joints (left, bottom), which were observed at 52 days. Mean histological severity, as assessed by the extent of inflammatory cell infiltration (IF), synovial hyperplasia (SH), and bone destruction (BD) on H&E staining, is also shown on the right. Scale bars: 200 μm. (C) Reduction of serum levels of the IgG antibody against type II collagen (anti-CII Ab) in mice injected with Ad-Ywhaz. Data are the mean ± SD arbitrary units (AU, n = 5). (D) mRNA expression levels of Ywhaz and proinflammatory cytokines (Il6 and Tnf) in the synovial tissues of CIA mice 52 days after treatment with Ad-Ywhaz or Ad-Con (n = 6 per group). Target gene expression levels were normalized to those of Gapdh (internal control). (E and F) Decrease in proinflammatory cytokine expression by Ad-Ywhaz. On day 52, lymph node (LN) or spleen cells were isolated from mice treated with Ad-Ywhaz (n = 6) or Ad-Con (n = 6), and then stimulated with 10 ng/mL LPS (E) or 1 μg/mL anti-CD3 plus anti-CD28 Abs (F) for indicated times; e.g., D2 indicates day 2. Levels of IL-6, TNF, and IL-17 in the culture supernatants were measured by ELISA. Data are the mean ± SEM for A, B, and D–F. *P < 0.05, **P < 0.01, ***P < 0.001 as determined by Student’s t test.