Genomic Multiple Sclerosis Risk Variants Modulate the Expression of the ANKRD55 - IL6ST Gene Region in Immature Dendritic Cells
Mena, Jorge (Instituto de Investigación Sanitaria Biocruces Bizkaia)
Alloza, Iraide (Instituto de Investigación Sanitaria Biocruces Bizkaia)
Tulloch Navarro, Raquel (Instituto de Investigación Sanitaria Biocruces Bizkaia)
Aldekoa, Ane (Instituto de Investigación Sanitaria Biocruces Bizkaia)
Díez García, Javier (Instituto de Investigación Sanitaria Biocruces Bizkaia)
Villanueva Etxebarria, Ane (Hospital de Galdakao (Usansolo, Biscaia))
Lindskog, Cecilia (Uppsala University)
Antigüedad, Alfredo (Instituto de Investigación Sanitaria Biocruces Bizkaia)
Boyero, Sabas (Instituto de Investigación Sanitaria Biocruces Bizkaia)
Mendibe-Bilbao, María del Mar (Instituto de Investigación Sanitaria Biocruces Bizkaia)
Álvarez de Arcaya, Amaya (Instituto de Investigación Sanitaria Bioaraba (Vitoria, País Basc))
Sánchez Menoyo, José Luis (Instituto de Investigación Sanitaria Biocruces Bizkaia)
Midaglia, Luciana (Hospital Universitari Vall d'Hebron)
Villarrubia, Noelia (Instituto Ramón y Cajal de Investigación Sanitaria (Madrid))
Malhotra, Sunny (Hospital Universitari Vall d'Hebron)
Montalban, Xavier (Hospital Universitari Vall d'Hebron)
Villar, Luisa M (Instituto Ramón y Cajal de Investigación Sanitaria (Madrid))
Comabella, Manuel (Hospital Universitari Vall d'Hebron)
Vandenbroeck, Koen (Basque Foundation for Science)
Universitat Autònoma de Barcelona

Data:	2022
Resum:	Intronic single-nucleotide polymorphisms (SNPs) in the ANKRD55 gene are associated with the risk for multiple sclerosis (MS) and rheumatoid arthritis by genome-wide association studies (GWAS). The risk alleles have been linked to higher expression levels of ANKRD55 and the neighboring IL6ST (gp130) gene in CD4 + T lymphocytes of healthy controls. The biological function of ANKRD55, its role in the immune system, and cellular sources of expression other than lymphocytes remain uncharacterized. Here, we show that monocytes gain capacity to express ANKRD55 during differentiation in immature monocyte-derived dendritic cells (moDCs) in the presence of interleukin (IL)-4/granulocyte-macrophage colony-stimulating factor (GM-CSF). ANKRD55 expression levels are further enhanced by retinoic acid agonist AM580 but downregulated following maturation with interferon (IFN)-γ and lipopolysaccharide (LPS). ANKRD55 was detected in the nucleus of moDC in nuclear speckles. We also analyzed the adjacent IL6ST, IL31RA, and SLC38A9 genes. Of note, in healthy controls, MS risk SNP genotype influenced ANKRD55 and IL6ST expression in immature moDC in opposite directions to that in CD4 + T cells. This effect was stronger for a partially correlated SNP, rs13186299, that is located, similar to the main MS risk SNPs, in an ANKRD55 intron. Upon analysis in MS patients, the main GWAS MS risk SNP rs7731626 was associated with ANKRD55 expression levels in CD4 + T cells. MoDC-specific ANKRD55 and IL6ST mRNA levels showed significant differences according to the clinical form of the disease, but, in contrast to healthy controls, were not influenced by genotype. We also measured serum sgp130 levels, which were found to be higher in homozygotes of the protective allele of rs7731626. Our study characterizes ANKRD55 expression in moDC and indicates monocyte-to-dendritic cell (Mo-DC) differentiation as a process potentially influenced by MS risk SNPs.
Ajuts:	Instituto de Salud Carlos III FIS-PI20/00123 Ministerio de Economía y Competitividad SAF2016-74891-R Instituto de Salud Carlos III FIS-PI18/00572
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan aquestes es distribueixin sota la mateixa llicència que regula l'obra original i es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	ANKRD55 ; IL6ST ; Sgp130 ; Multiple sclerosis ; Autoimmune
Publicat a:	Frontiers in immunology, Vol. 12 (january 2022) , ISSN 1664-3224

DOI: 10.3389/fimmu.2021.816930
PMID: 35111166

17 p, 8.0 MB

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