Background/Purpose: Serum amyloid A (SAA) is an acute phase protein and its serum levels may increase up to 1000-fold over normal levels during inflammation, triggering perpetual inflammatory responses. The level of SAA has been reported to have a correlation with rheumatoid arthritis (RA) symptoms. However, the direct role of SAA in the RA pathogenesis remains unclear. In this study, we have identified that SAA contributes to the activation of macrophages through induction of nuclear factor of activated T cells 5 (NFAT5), resulting in the aggravation of arthritic symptoms.

Methods: Expression of NFAT5 was examined in the SAA-treated macrophages using Western blot analysis and immunofluochemistry. The transcriptional activation of NFAT5 was measured by luciferase reporter assay and Matrigel assay. To find the receptor and signaling pathway involved in the SAA-induced NFAT5 expression, chemical inhibitors and genetically deficient macrophages were used. The cell migrations were compared between wild type and NFAT5 knock-down or knock-out macrophages by using transwell migration assay, wound-healing assay and air-pouch mouse model. To confirm the importance of SAA-NFAT5 axis in vivo, we injected SAA into the arthritis mouse model induced by injection of methylated-bovine serum albumin/interlukin-1β (mBSA/IL-1β).

Results: SAA induced the expression and activation of NFAT5 in macrophages, which is mediated by TLR2 and TLR4 on their surface. MAPKs and PI3K signaling pathways, especially JNK1/2, were involved in the NFAT5 expression induced by SAA treatment. The induced NFAT5 contributed to the cytoskeletal rearrangement in macrophages, thereby leading to the cell migration in vitro and in vivo. Moreover, SAA injection aggravated disease severity, including increased macrophages, in the joints of mBSA/IL-1β-induced arthritis.

Conclusion: Our data show novel findings that SAA could induce the activation and migration of macrophages by stimulating the expression and activity of NFAT5 through TLR2/4 and MAPKs signaling pathways. Moreover, Increased SAA could contribute to the aggravation of arthritis symptoms in the mouse model. Thus, targeting SAA-NFAT5 axis may potentially be of therapeutic value in chronic inflammatory diseases accompanied by elevated SAA levels, such as rheumatoid arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/serum-amyloid-a-aggravates-rheumatoid-arthritis-by-activating-nfat5-mediated-migration-of-macrophages/