Amino Acids Fueling Fibroblast‐Like Synoviocyte Activation and Arthritis By Regulating Chemokine Expression and Leukocyte Migration

Abstract

ObjectiveTo analyze the impact of amino acid (AA) availability on the inflammatory response in arthritis.MethodsWe 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.ResultsDeprivation 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.ConclusionAA‐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.image

Inflammatory tissue priming: novel insights and therapeutic opportunities for inflammatory rheumatic diseases

“…The metabolite mevalonate, which is part of the cholesterol synthesis pathway, recently emerged as the mediator of training via activation of mTOR and subsequent histone modifications in inflammation-related genes 295. Food constituents also heavily influence the activity of tissue-resident cells, contributing to tissue maladaptation, for example, T resident memory cells in the skin and the joints show especially high uptake of free fatty acids for fatty acid oxidation,137 296 and arthritogenic activation and chemokine expression in SFs is dependent on external supply of amino acids 297…”

“…Other prominent systemic metabolic consequences of dietary restriction include changes in lipid and amino acid metabolism, including elevated levels of polyunsaturated free fatty acids and decreased concentrations of methionine352 and activation of AMPK and PPARα signalling,344 increasing catabolic and mitochondrial metabolism and dampening of inflammation. Very recently, mice receiving a low protein diet were shown to develop milder K/BxN serum transfer arthritis 297…”