Extracellular sulfatase-2 is overexpressed in rheumatoid arthritis and mediates the TNF-α-induced inflammatory activation of synovial fibroblasts.

Autor:	Siegel RJ; Department of Pharmaceutical Sciences, Washington State University College of Pharmacy and Pharmaceutical Sciences, Spokane, WA, USA., Singh AK; Department of Pharmaceutical Sciences, Washington State University College of Pharmacy and Pharmaceutical Sciences, Spokane, WA, USA., Panipinto PM; Department of Pharmaceutical Sciences, Washington State University College of Pharmacy and Pharmaceutical Sciences, Spokane, WA, USA., Shaikh FS; Department of Pharmaceutical Sciences, Washington State University College of Pharmacy and Pharmaceutical Sciences, Spokane, WA, USA., Vinh J; Department of Pharmaceutical Sciences, Washington State University College of Pharmacy and Pharmaceutical Sciences, Spokane, WA, USA., Han SU; Department of Pharmaceutical Sciences, Washington State University College of Pharmacy and Pharmaceutical Sciences, Spokane, WA, USA., Kenney HM; Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA., Schwarz EM; Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA., Crowson CS; Department of Quantitative Health Sciences and Division of Rheumatology, Mayo Clinic, Rochester, MN, USA., Khuder SA; Department of Medicine and Public Health, University of Toledo, Toledo, OH, USA., Khuder BS; Department of Pathology and Laboratory Medicine, Phoenix Children's Hospital, Phoenix, AZ, USA., Fox DA; Department of Medicine, Division of Rheumatology and Clinical Autoimmunity Center of Excellence, University of Michigan Medical System, Ann Arbor, MI, USA., Ahmed S; Department of Pharmaceutical Sciences, Washington State University College of Pharmacy and Pharmaceutical Sciences, Spokane, WA, USA. salah.ahmed@wsu.edu.; Division of Rheumatology, University of Washington School of Medicine, Seattle, WA, USA. salah.ahmed@wsu.edu.
Jazyk:	angličtina
Zdroj:	Cellular & molecular immunology [Cell Mol Immunol] 2022 Oct; Vol. 19 (10), pp. 1185-1195. Date of Electronic Publication: 2022 Sep 07.
DOI:	10.1038/s41423-022-00913-x
Abstrakt:	Extracellular sulfatase-2 (Sulf-2) influences receptor-ligand binding and subsequent signaling by chemokines and growth factors, yet Sulf-2 remains unexplored in inflammatory cytokine signaling in the context of rheumatoid arthritis (RA). In the present study, we characterized Sulf-2 expression in RA and investigated its potential role in TNF-α-induced synovial inflammation using primary human RA synovial fibroblasts (RASFs). Sulf-2 expression was significantly higher in serum and synovial tissues from patients with RA and in synovium and serum from hTNFtg mice. RNA sequencing analysis of TNF-α-stimulated RASFs showed that Sulf-2 siRNA modulated ~2500 genes compared to scrambled siRNA. Ingenuity Pathway Analysis of RNA sequencing data identified Sulf-2 as a primary target in fibroblasts and macrophages in RA. Western blot, ELISA, and qRT‒PCR analyses confirmed that Sulf-2 knockdown reduced the TNF-α-induced expression of ICAM1, VCAM1, CAD11, PDPN, CCL5, CX3CL1, CXCL10, and CXCL11. Signaling studies identified the protein kinase C-delta (PKCδ) and c-Jun N-terminal kinase (JNK) pathways as key in the TNF-α-mediated induction of proteins related to cellular adhesion and invasion. Knockdown of Sulf-2 abrogated TNF-α-induced RASF proliferation. Sulf-2 knockdown with siRNA and inhibition by OKN-007 suppressed the TNF-α-induced phosphorylation of PKCδ and JNK, thereby suppressing the nuclear translocation and DNA binding activity of the transcription factors AP-1 and NF-κBp65 in human RASFs. Interestingly, Sulf-2 expression positively correlated with the expression of TNF receptor 1, and coimmunoprecipitation assays demonstrated the binding of these two proteins, suggesting they exhibit crosstalk in TNF-α signaling. This study identified a novel role of Sulf-2 in TNF-α signaling and the activation of RA synoviocytes, providing the rationale for evaluating the therapeutic targeting of Sulf-2 in preclinical models of RA. (© 2022. The Author(s), under exclusive licence to CSI and USTC.)
Databáze:	MEDLINE
Externí odkaz:	Full text from SpringerLink