Serum amyloid A expression in liver promotes synovial macrophage activation and chronic arthritis via NFAT5
Meiling Li, … , Donghyun Kim, Wan-Uk Kim
Meiling Li, … , Donghyun Kim, Wan-Uk Kim
Published March 1, 2024
Citation Information: J Clin Invest. 2024;134(5):e167835. https://doi.org/10.1172/JCI167835.
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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 6

IL-1β–induced arthritis progresses to rheumatoid pathology by repeated challenges with SAA, whereas it is blocked by anti-SAA Ab.

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IL-1β–induced arthritis progresses to rheumatoid pathology by repeated c...
(A) SAA-accelerated arthritis was induced as in Supplemental Figure 8A. After 1 week, SAA (5 μg) or vehicle alone was additionally injected into the affected joint once a week for a total of 3 times. At day 28, arthritis severity was scored on a scale of 0 to 3, depending on the extent of inflammatory cell infiltration, synovial hyperplasia, and bone destruction. The bar graph represents mean ± SD. **P < 0.01 by Mann Whitney U test. (B) The joint pathology showing resolution of arthritis in mice singly injected with SAA versus ‘pannus formation’ (arrows) in addition to a more severe bony erosion and invasion (arrowheads) in mice receiving multiple injections of SAA. The bar graph represents mean ± SD of pannus formation score. ***P < 0.001 by Mann Whitney U test. (C) The degree of angiogenesis assessed by immunostaining for vWF using anti-vWF Ab. The bar graph represents mean ± SD of the stained area (mm2). **P < 0.01 by unpaired t test. (D) Toluidine blue stain for cartilage damage of the affected (knee) joint of mice with single versus multiple SAA injection. The bar graph indicates mean ± SD. ****P < 0.0001 by unpaired t test. (E) Amelioration of IL-1β-induced arthritis by anti-SAA Ab. Neutralizing Ab to SAA (1mg/kg) was i.p. injected on days 1 and 2 into the mice with a standard form of IL-1β–induced arthritis (IL-1β: 250 ng × 3, no SAA injection). The same concentration of isotype control IgG was used as a control. At day 7, arthritis severity was evaluated. The bar graph represents mean ± SD. *P < 0.05 and **P < 0.01 by Mann Whitney U test. Data in A and E are representative of 2 independent experiments.