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 8

Liver is one of the major sources of SAA production in inflammatory arthritis.

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Liver is one of the major sources of SAA production in inflammatory arth...
(A) Levels of SAA in paired sera and synovial fluids isolated simultaneously from patients with RA (n = 25), as determined by ELISA. Data are mean ± SD. ****P < 0.0001 by Wilcoxon matched pairs signed rank test. (B and C) qPCR analysis of mSaa1, mSaa2, and mSaa3 mRNA expression levels in the liver and joint tissues of mice injected i.p. with 10 mg/kg of LPS (B) or in those of mice injected with mBSA (200 μg, 1 × on day 0) and/or IL-1β (250 ng, 3 × on days 0, 1, and 2) (C). Data are mean ± SD. *P < 0.05, **P < 0.01, and ***P < 0.001by Kruskal-Wallis test for mSaa1 and mSaa2 (B), Brown–Forsythe and Welch’s ANOVA test for mSaa3 (B), 2-way ANOVA test for mSaa1 and mSaa3 (C), and Friedman’s test for mSaa2 (C). Comparison of numerical data between groups were performed using the unpaired t test, Welch’s t test, or Mann-Whitney U test. Data are representative of 2 independent experiments. (D) SAA production from cultured hepatocytes and synoviocytes. Hepatocytes (1 × 105/well) and fibroblast-like synoviocytes (5 × 104/well), isolated from C57BL/6 mice, were stimulated with LPS (10 ng/mL), IL-6 (10 ng/mL), and IL-1β (10 ng/mL) for the indicated times. The concentration of SAA in the culture supernatants was determined by ELISA. Data are mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 by 1-way ANOVA with Tukey’s multiple comparisons test.