Serum amyloid A expression in liver promotes synovial macrophage activation and chronic arthritis via NFAT5
Meiling Li, Yu-Mi Kim, Jung Hee Koh, Jihyun Park, H. Moo Kwon, Jong-Hwan Park, Jingchun Jin, Youngjae Park, Donghyun Kim, Wan-Uk Kim
Meiling Li, Yu-Mi Kim, Jung Hee Koh, Jihyun Park, H. Moo Kwon, Jong-Hwan Park, Jingchun Jin, Youngjae Park, Donghyun Kim, Wan-Uk Kim
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Research Article Autoimmunity Inflammation

Serum amyloid A expression in liver promotes synovial macrophage activation and chronic arthritis via NFAT5

Abstract

Nuclear factor of activated T-cells 5 (NFAT5), an osmo-sensitive transcription factor, can be activated by isotonic stimuli, such as infection. It remains unclear, however, whether NFAT5 is required for damage-associated molecular pattern–triggered (DAMP-triggered) inflammation and immunity. Here, we found that several DAMPs increased NFAT5 expression in macrophages. In particular, serum amyloid A (SAA), primarily generated by the liver, substantially upregulated NFAT5 expression and activity through TLR2/4-JNK signalling pathway. Moreover, the SAA-TLR2/4-NFAT5 axis promoted migration and chemotaxis of macrophages in an IL-6– and chemokine ligand 2–dependent (CCL2-dependent) manner in vitro. Intraarticular injection of SAA markedly accelerated macrophage infiltration and arthritis progression in mice. By contrast, genetic ablation of NFAT5 or TLR2/4 rescued the pathology induced by SAA, confirming the SAA-TLR2/4-NFAT5 axis in vivo. Myeloid-specific depletion of NFAT5 also attenuated SAA-accelerated arthritis. Of note, inflammatory arthritis in mice strikingly induced SAA overexpression in the liver. Conversely, forced overexpression of the SAA gene in the liver accelerated joint damage, indicating that the liver contributes to bolstering chronic inflammation at remote sites by secreting SAA. Collectively, this study underscores the importance of the SAA-TLR2/4-NFAT5 axis in innate immunity, suggesting that acute phase reactant SAA mediates mutual interactions between liver and joints and ultimately aggravates chronic arthritis by enhancing macrophage activation.

Authors

Meiling Li, Yu-Mi Kim, Jung Hee Koh, Jihyun Park, H. Moo Kwon, Jong-Hwan Park, Jingchun Jin, Youngjae Park, Donghyun Kim, Wan-Uk Kim

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Figure 10

Serial monitoring of serum SAA levels before and after treatment with antirheumatic drugs in patients with RA.

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Serial monitoring of serum SAA levels before and after treatment with an...
(A) Correlation between SAA level and disease activity of RA. Serum SAA levels were measured by ELISA both before and 6 months after treatment with antirheumatic drugs, including TNFi, Tocilizumab, an anti-IL-6 receptor Ab, JAKi, and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) (See Supplemental Table 1 for more details). At the time of blood sampling, the DAS28, which represents RA activity, was assessed. The correlation analysis was performed using the Spearman test. (B) The ΔSAA from baseline to 6-month follow-up according to the treatment response. Good, moderate, and no response were defined according to EULAR response criteria. ****P < 0.0001 by Wilcoxon matched pairs signed rank test. (C) Comparison of ΔSAA levels depending on the kinds of antirheumatic drugs, including TNFi, Tocilizumab, JAKi, and csDMARDs. Data are mean ± SD. *P < 0.05 and **P < 0.01, by Kruskal-Wallis test with Dunn’s multiple comparisons test. (D) Positive correlations of ΔSAA with ΔCRP, ΔESR, and ΔDAS28. The correlation analysis was performed using the Spearman test.