Nuclear Receptor Subfamily 4A Signaling as a Key Disease Pathway of CD1c+ Dendritic Cell Dysregulation in Systemic Sclerosis.

Autor:	Servaas NH; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Hiddingh S; Center for Translational Immunology and Ophthalmo-Immunology Unit, University Medical Center Utrecht, Utrecht, The Netherlands., Chouri E; Center for Translational Immunology and Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Wichers CGK; Center for Translational Immunology and Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Affandi AJ; Center for Translational Immunology and Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Ottria A; Center for Translational Immunology and Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Bekker CPJ; Center for Translational Immunology and Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Cossu M; Center for Translational Immunology and Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Silva-Cardoso SC; Center for Translational Immunology and Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., van der Kroef M; Center for Translational Immunology and Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Hinrichs AC; Center for Translational Immunology and Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Carvalheiro T; Center for Translational Immunology and Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Vazirpanah N; Center for Translational Immunology and Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Beretta L; Scleroderma Unit, Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy., Rossato M; Department of Biotechnology, University of Verona, Verona, Italy., Bonte-Mineur F; Department of Rheumatology and Clinical Immunology, Maasstad Hospital, Rotterdam, The Netherlands., Radstake TRDJ; Center for Translational Immunology and Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Kuiper JJW; Center for Translational Immunology and Ophthalmo-Immunology Unit, University Medical Center Utrecht, Utrecht, The Netherlands., Boes M; Department of Pediatrics, University Medical Center Utrecht, Utrecht University, The Netherlands., Pandit A; Center for Translational Immunology and Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Jazyk:	angličtina
Zdroj:	Arthritis & rheumatology (Hoboken, N.J.) [Arthritis Rheumatol] 2023 Feb; Vol. 75 (2), pp. 279-292. Date of Electronic Publication: 2022 Dec 08.
DOI:	10.1002/art.42319
Abstrakt:	Objective: This study was undertaken to identify key disease pathways driving conventional dendritic cell (cDC) alterations in systemic sclerosis (SSc). Methods: Transcriptomic profiling was performed on peripheral blood CD1c+ cDCs (cDC2s) isolated from 12 healthy donors and 48 patients with SSc, including all major disease subtypes. We performed differential expression analysis for the different SSc subtypes and healthy donors to uncover genes dysregulated in SSc. To identify biologically relevant pathways, we built a gene coexpression network using weighted gene correlation network analysis. We validated the role of key transcriptional regulators using chromatin immunoprecipitation (ChIP) sequencing and in vitro functional assays. Results: We identified 17 modules of coexpressed genes in cDCs that correlated with SSc subtypes and key clinical traits, including autoantibodies, skin score, and occurrence of interstitial lung disease. A module of immunoregulatory genes was markedly down-regulated in patients with the diffuse SSc subtype characterized by severe fibrosis. Transcriptional regulatory network analysis performed on this module predicted nuclear receptor 4A (NR4A) subfamily genes (NR4A1, NR4A2, NR4A3) as the key transcriptional regulators of inflammation. Indeed, ChIP-sequencing analysis indicated that these NR4A members target numerous differentially expressed genes in SSc cDC2s. Inclusion of NR4A receptor agonists in culture-based experiments provided functional proof that dysregulation of NR4As affects cytokine production by cDC2s and modulates downstream T cell activation. Conclusion: NR4A1, NR4A2, and NR4A3 are important regulators of immunosuppressive and fibrosis-associated pathways in SSc cDCs. Thus, the NR4A family represents novel potential targets to restore cDC homeostasis in SSc. (© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)
Databáze:	MEDLINE
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