Vitamin D receptor, STAT3, and TET2 cooperate to establish tolerogenesis
Català-Moll, Francesc (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Ferreté Bonastre, Anna G. (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Godoy-Tena, Gerard (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Morante-Palacios, Octavio (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Ciudad, Laura (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Barberà, Laura (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Fondelli, Federico (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Martínez Cáceres, Eva María (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Rodríguez-Ubreva, Javier (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Li, Tianlu (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Ballestar, Esteban (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)

Date:	2022
Abstract:	The active form of vitamin D, 1,25-dihydroxyvitamin D3, induces a stable tolerogenic phenotype in dendritic cells (DCs). This process involves the vitamin D receptor (VDR), which translocates to the nucleus, binds its cognate genomic sites, and promotes epigenetic and transcriptional remodeling. In this study, we report the occurrence of vitamin D-specific DNA demethylation and transcriptional activation at VDR binding sites associated with the acquisition of tolerogenesis in vitro. Differentiation to tolerogenic DCs associates with activation of the IL-6-JAK-STAT3 pathway. We show that JAK2-mediated STAT3 phosphorylation is specific to vitamin D stimulation. VDR and the phosphorylated form of STAT3 interact with each other to form a complex with methylcytosine dioxygenase TET2. Most importantly, pharmacological inhibition of JAK2 reverts vitamin D-induced tolerogenic properties of DCs. This interplay among VDR, STAT3, and TET2 opens up possibilities for modulating DC immunogenic properties in clinics.
Grants:	Agencia Estatal de Investigación PID2020-117212RB-I00 Instituto de Salud Carlos III PI17/01521 Instituto de Salud Carlos III PI20/01313
Note:	We are very grateful to Dr. José Luis Sardina for useful feedback. We thank CERCA Programme/Generalitat de Catalunya and the Josep Carreras Foundation for institutional support. E.B. was funded by the Spanish Ministry of Science and Innovation (MICINN ; grant number PID2020-117212RB-I00/AEI/10.13038/501100011033). E.M.-C. is funded with RESTORE project (EU H2020 Research and Innovation Programme, number 779316) and Spanish projects PI17/01521 and PI20/01313, integrated in the Plan Nacional de I+D+I and co-supported by the ISCIII-Subdirección General de Evaluación and FEDER. O.M.-P. holds an i-PFIS PhD fellowship (grant number IFI17/00034) from Acción Estratégica en Salud 2013-2016 ISCIII, co-financed by Fondo Social Europeo. F.F. holds a PhD fellowship from the INsTRuCT Consortium, which receives. Innovative Training Network subsidy from the EU H2020 program.
Note:	We are very grateful to Dr. Jos? Luis Sardina for useful feedback. We thank CERCA Programme/Generalitat de Catalunya and the Josep Carreras Foundation for institutional support. E.B. was funded by the Spanish Ministry of Science and Innovation (MICINN; grant number PID2020-117212RB-I00/AEI/10.13038/501100011033). E.M.-C. is funded with RESTORE project (EU H2020 Research and Innovation Programme, number 779316) and Spanish projects PI17/01521 and PI20/01313, integrated in the Plan Nacional de I+D+I and co-supported by the ISCIII-Subdirecci?n General de Evaluaci?n and FEDER. O.M.-P. holds an i-PFIS PhD fellowship (grant number IFI17/00034) from Acci?n Estrat?gica en Salud 2013?2016 ISCIII, co-financed by Fondo Social Europeo. F.F. holds a PhD fellowship from the INsTRuCT Consortium, which receives. Innovative Training Network subsidy from the EU H2020 program. F.C.-M. and E.B. conceived and designed the study; F.C.-M. A.G.F.-B. G.G.-T. O.M.-P. L.C. L.B. F.F. and T.L. performed the differentiation, chromatin immunoprecipitation, co-immunoprecipitation experiments, and immunological assays; F.C.-M. performed the bioinformatic analyses; F.C.-M. A.G.F.-B. G.G.-T. E.M.-C. and E.B. analyzed results; J.R.-U. and E.B. supervised the study; F.C.-M. T.L. and E.B. wrote the manuscript; all authors participated in discussions and interpreting the results. The authors declare no competing interests.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Tolerogenesis ; Dendritic cells ; Vitamin D ; VDR ; STAT3 ; TET2 ; IL-6-JAK-STAT ; DNA methylation ; JAK2
Published in:	Cell reports, Vol. 38 Núm. 3 (18 2022) , p. 110244, ISSN 2211-1247

DOI: 10.1016/j.celrep.2021.110244

33 p, 9.9 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Josep Carreras Leukaemia Research Institute
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