Identification of a novel epigenetic code, histone H1 fucosylation, and its roles in macrophage plasticity in rheumatoid arthritis (IRM7P.491)

Abstract

Abstract Macrophages (MΦ) are key players in rheumatoid arthritis (RA). High plasticity renders MΦ an attractive tool for studying epigenetic reprogramming. We have observed a highly positive correlation between TNFα and fucosylation catalyzing enzymes, fucosyltransferases (FUTs) 1, 2, 3, 4, 5, 6, 7, 9, 10, 11 (p=0.0001) in human RA synovia; these FUTs are predominantly detected in M1 inflammatory MΦ but not M2 MΦ and T cells from RA synovial fluid. A fucosylation inhibitor, 2-Deoxy-D-galactose (2-D-gal) precluded collagen II-induced arthritis in DBA/1J mice (scores 9.5±1.7 vs 0.5± 0.3, p<0.01) with reduced M1 MΦ in draining LN, decreased TNF-α and anti-CII in the serum (p<0.05).Ulex Europaeus Agglutinin I (UEA 1) affinity chromatography coupled to mass spectrometry indicated that the linker Histone H1, but not core histone H 2-4, is the major protein that modified by a fucose-α-(1-2)-gal moiety in M1 MΦ. Disrupting this moiety by 2-D-gal skewed the differentiation of M1 MΦ toward M2 anti-inflammatory phenotype with a reprogrammed gene expression, including i) robustly upregulated Il10, Arg1, and Megf8 (p<0.01) (M2 markers); ii) downregulated Ifnγ and Il6 (p<0.05) (M1 markers); iii) inhibited Actin and its associated molecules including Ahnak and Cap1, and suppressed the antigen presentation of M1 MΦ phenotype (p<0.01). We uncovered Histone 1 fucosylation as a novel epigenetic code that orchestrates MΦ transcriptome reprogramming and renders it an attractive target for RA therapy.