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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 Article has an altmetric score of 5

Dynamic transcriptome analysis unveils key proresolving factors of chronic inflammatory arthritis

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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 1

Dynamic expression changes of genes and cellular processes associated with resolution of CIA.

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Dynamic expression changes of genes and cellular processes associated wi...
(A) Arthritis score (bottom) evaluated at 2-day intervals during CIA progression. Data are the mean ± SEM (n = 8 mice per time point). Induction (I), peak (P), and resolution (R) phases (6, 9, and 15 weeks, respectively) are indicated by arrows. Representative arthritic joints (top) at the 3 phases are shown. (B) Quantitative real-time polymerase chain reaction (qRT-PCR) assays for proinflammatory (Ptgs2, Il6, and Il1b) and antiinflammatory cytokines (Il4, Il10, and Tgfb1) before immunization (N) and at the I, P, and R phase after the immunization. Expression levels of each gene at the 4 phases (n = 4–8 per phase) are shown using box-and-whisker plots. (C) Resolution-related clusters (C1–C6) of genes (columns in the heat maps). Colors represent up- (red) and downregulation (blue) of the genes in the indicated clusters. Log2-fold changes of the genes from the comparisons of P/I (first and second rows) and R/P (third and fourth rows) are shown for 2 replicates in each condition. U, D, and N in parentheses denote up- and downregulation and no expression changes, respectively; e.g., UN (for C1) indicates upregulation in the comparison of P/I and no expression change in the comparison of R/P. The numbers in parentheses denote the numbers of DEGs in the individual clusters. (D) GOBPs enriched by the genes in C1–C6. Color bars represent the gradients of Z scores (enrichment significance) defined as Z = N–1(1 – P), where N–1(·) is the inverse standard normal distribution and P is the enrichment P value. (E) qRT-PCR assays for the representative genes. For qRT-PCR assays, mRNA expression levels of each gene (n ≥ 8 per group) were normalized to that of Gapdh (internal control) using the 2–ΔΔCt method. In the box-and-whisker plots, the boxes display the lower, median, and upper quartiles and the whiskers represent the minimum and maximum values. *P < 0.05, **P < 0.01, ***P < 0.001 by 1-way ANOVA with a post hoc test (Tukey’s correction; B) or Student’s t test (E).

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