Amino acids fuel fibroblast-like synoviocyte activation and arthritis by regulating chemokine expression and leukocyte migration.

To analyze the impact of amino acid (AA) availability on the inflammatory response in arthritis. We stimulated rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) with TNF in the presence or absence of proteinogenic AAs and measured their response by QuantSeq 3' mRNA sequencing, qPCR and ELISA. Signal transduction events were determined by Western Blot. We performed K/BxN serum transfer arthritis in mice receiving normal and a low protein diet and analyzed arthritis clinically and histologically. Deprivation of AAs decreased the expression of a specific subset of genes, including the chemokines CXCL10, CCL2 and CCL5 in TNF-stimulated FLS. Mechanistically, the presence of AAs was required for the TNF-induced activation of an IRF1-STAT1 signaling circuit that drives the expression of chemotactic factors. The expression of IRF1 and the IRF1-dependent gene set in FLS was highly correlated with the presence of inflammatory cells in human RA, emphasizing the important role of this AA-dependent pathway in inflammatory cell recruitment to the synovial tissue. Finally, we show that mice receiving a low protein diet expressed less IRF1 in the inflamed synovium and consequently developed reduced clinical and histological signs of arthritis. AA-deprivation reduces the severity of arthritis by suppressing the expression of IRF1-STAT1-driven chemokines, which are crucial for leukocyte recruitment to the arthritic joint. Overall, our study provides novel insights into critical determinants of inflammatory arthritis and may pave the way for dietary intervention trials in RA.

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