The extracellular heparan sulfatase SULF2 limits myeloid IFNβ signaling and Th17 responses in inflammatory arthritis

Heparan sulfate (HS) proteoglycans are important regulators of cellular responses to soluble mediators such as chemokines, cytokines and growth factors. We profiled changes in expression of genes encoding HS core proteins, biosynthesis enzymes and modifiers during macrophage polarisation, and found that the most highly regulated gene was Sulf2 , an extracellular HS 6-O-sulfatase that was markedly downregulated in response to pro-inflammatory stimuli. We then generated Sulf2 +/- bone marrow chimeric mice and examined inflammatory responses in antigen-induced arthritis, as a model of rheumatoid arthritis. Resolution of inflammation was impaired in myeloid Sulf2 +/- chimeras, with elevated joint swelling and increased abundance of pro-arthritic Th17 cells in synovial tissue. Transcriptomic and in vitro analyses indicated that Sulf2 deficiency increased type I interferon signaling in bone marrow-derived macrophages, leading to elevated expression of the Th17-inducing cytokine IL-6. This establishes that dynamic remodeling of HS by Sulf2 limits type I interferon signaling in macrophages, and so protects against Th17-driven pathology. ### Competing Interest Statement The authors have declared no competing interest. * AIA : antigen-induced arthritis APRIL : A Proliferation-Inducing Ligand BMDM : bone marrow-derived macrophages DCs : dendritic cells FBS : fetal bovine serum FSL-1 : fibroblast-stimulating lipopeptide-1 FMO : fluorescence minus one GM-CSF : granulocyte-macrophage colony-stimulating factor HS : heparan sulfate IFN : interferon IFNAR1 : interferon-alpha/beta receptor alpha chain IFNAR2 : interferon-alpha/beta receptor beta chain KEGG : Kyoto Encyclopedia of Genes and Genomes LC3 : microtubule-associated protein light chain 3 LPS : lipopolysaccharide mBSA : methylated bovine serum albumin M-CSF : macrophage colony-stimulating factor MFI : mean fluorescence intensity MOI : multiplicity of infection OVA : ovalbumin Pam3CSK4 : N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-[R]-cysteinyl-[S]-seryl-[S]-lysyl-[S]-lysyl-[S]-lysyl-[S]-lysine PCA : principal component analysis PMA : phorbol 12-myristate 13-acetate polyinosinic:polycytidylic acid : poly (I:C) RPMI : Roswell Park Memorial Institute 1640 medium SULF2 : sulfatase 2 TaqMan Low-Density Array : TLDA TLR : Toll-like receptor transforming growth factor beta (TGFβ) WT : wild-type