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Serum amyloid A expression in liver promotes synovial macrophage activation and chronic arthritis via NFAT5
- Source :
- Journal of Clinical Investigation. March 1, 2024, Vol. 134 Issue 5
- Publication Year :
- 2024
-
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.<br />Introduction Macrophages play a pivotal role in the pathogenesis of chronic inflammatory diseases, such as rheumatoid arthritis (RA), with broad proinflammatory, destructive, and remodeling capabilities (1, 2). Similar to other [...]
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 134
- Issue :
- 5
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.788885255
- Full Text :
- https://doi.org/10.1172/JCI167835