The Epigenetic Reader Protein SP140 Regulates Dendritic Cell Activation, Maturation and Tolerogenic Potential

Author:

Ghiboub Mohammed12ORCID,Bell Matthew2ORCID,Sinkeviciute Dovile2ORCID,Prinjha Rab K.2,de Winther Menno P. J.34ORCID,Harker Nicola R.2,Tough David F.2ORCID,de Jonge Wouter J.15ORCID

Affiliation:

1. Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology, Endocrinology Metabolism, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 BK Amsterdam, The Netherlands

2. Immunology Research Unit, Medicines Research Centre, GlaxoSmithKline, Stevenage SG1 2NY, UK

3. Department of Medical Biochemistry, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands

4. Department of Medicine, Institute for Cardiovascular Prevention (IPEK), 80336 Munich, Germany

5. Department of Surgery, University of Bonn, 53127 Bonn, Germany

Abstract

SP140 is an epigenetic reader protein expressed predominantly in immune cells. GWAS studies have shown an association between SP140 single nucleotide polymorphisms (SNPs) and diverse autoimmune and inflammatory diseases, suggesting a possible pathogenic role for SP140 in immune-mediated diseases. We previously demonstrated that treatment of human macrophages with the novel selective inhibitor of the SP140 protein (GSK761) reduced the expression of endotoxin-induced cytokines, implicating a role of SP140 in the function of inflammatory macrophages. In this study, we investigated the effects of GSK761 on in vitro human dendritic cell (DC) differentiation and maturation, assessing the expression of cytokines and co-stimulatory molecules and their capacity to stimulate T-cell activation and induce phenotypic changes. In DCs, lipopolysaccharide (LPS) stimulation induced an increase in SP140 expression and its recruitment to transcription start sites (TSS) of pro-inflammatory cytokine genes. Moreover, LPS-induced cytokines such as TNF, IL-6, and IL-1β were reduced in GSK761- or SP140 siRNA- treated DCs. Although GSK761 did not significantly affect the expression of surface markers that define the differentiation of CD14+ monocytes into immature DCs (iDCs), subsequent maturation of iDCs to mature DCs was significantly inhibited. GSK761 strongly reduced expression of the maturation marker CD83, the co-stimulatory molecules CD80 and CD86, and the lipid-antigen presentation molecule CD1b. Finally, when the ability of DCs to stimulate recall T-cell responses by vaccine-specific T cells was assessed, T cells stimulated by GSK761-treated DCs showed reduced TBX21 and RORA expression and increased FOXP3 expression, indicating a preferential generation of regulatory T cells. Overall, this study suggests that SP140 inhibition enhances the tolerogenic properties of DCs, supporting the rationale of targeting SP140 in autoimmune and inflammatory diseases where DC-mediated inflammatory responses contribute to disease pathogenesis.

Funder

European Union’s Horizon 2020 research and innovation program

Publisher

MDPI AG

Subject

Microbiology (medical),Molecular Biology,General Medicine,Microbiology

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