Genomic Multiple Sclerosis Risk Variants Modulate the Expression of the ANKRD55–IL6ST Gene Region in Immature Dendritic Cells
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)...
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Frontiers Media S.A.
2022-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.816930/full |
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| author | Jorge Mena Iraide Alloza Raquel Tulloch Navarro Ane Aldekoa Javier Díez García Ane Villanueva Etxebarria Ane Villanueva Etxebarria Ane Villanueva Etxebarria Cecilia Lindskog Alfredo Antigüedad Sabas Boyero María del Mar Mendibe-Bilbao Amaya Álvarez de Arcaya José Luis Sánchez Menoyo Luciana Midaglia Noelia Villarrubia Sunny Malhotra Xavier Montalban Luisa María Villar Manuel Comabella Koen Vandenbroeck Koen Vandenbroeck Koen Vandenbroeck |
| author_facet | Jorge Mena Iraide Alloza Raquel Tulloch Navarro Ane Aldekoa Javier Díez García Ane Villanueva Etxebarria Ane Villanueva Etxebarria Ane Villanueva Etxebarria Cecilia Lindskog Alfredo Antigüedad Sabas Boyero María del Mar Mendibe-Bilbao Amaya Álvarez de Arcaya José Luis Sánchez Menoyo Luciana Midaglia Noelia Villarrubia Sunny Malhotra Xavier Montalban Luisa María Villar Manuel Comabella Koen Vandenbroeck Koen Vandenbroeck Koen Vandenbroeck |
| author_sort | Jorge Mena |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T18:20:39Z |
| format | Article |
| id | doaj.art-1cbafeb9203e4802bd402f1e6a4fab4a |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-11T18:20:39Z |
| publishDate | 2022-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-1cbafeb9203e4802bd402f1e6a4fab4a2022-12-22T04:09:47ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-01-011210.3389/fimmu.2021.816930816930Genomic Multiple Sclerosis Risk Variants Modulate the Expression of the ANKRD55–IL6ST Gene Region in Immature Dendritic CellsJorge Mena0Iraide Alloza1Raquel Tulloch Navarro2Ane Aldekoa3Javier Díez García4Ane Villanueva Etxebarria5Ane Villanueva Etxebarria6Ane Villanueva Etxebarria7Cecilia Lindskog8Alfredo Antigüedad9Sabas Boyero10María del Mar Mendibe-Bilbao11Amaya Álvarez de Arcaya12José Luis Sánchez Menoyo13Luciana Midaglia14Noelia Villarrubia15Sunny Malhotra16Xavier Montalban17Luisa María Villar18Manuel Comabella19Koen Vandenbroeck20Koen Vandenbroeck21Koen Vandenbroeck22Inflammation & Biomarkers Group, Biocruces-Bizkaia Health Research Institute, Barakaldo, SpainInflammation & Biomarkers Group, Biocruces-Bizkaia Health Research Institute, Barakaldo, SpainInflammation & Biomarkers Group, Biocruces-Bizkaia Health Research Institute, Barakaldo, SpainInflammation & Biomarkers Group, Biocruces-Bizkaia Health Research Institute, Barakaldo, SpainMicroscopy Facility, Biocruces-Bizkaia Health Research Institute, Barakaldo, SpainKronikgune Institute for Health Services Research, Barakaldo, SpainHealth Service Research Network on Chronic Diseases Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), Bizkaia, SpainOsakidetza-Basque Health Service, Research Unit, Galdakao University Hospital, Galdakao, SpainDepartment of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, SwedenDepartment of Neurology, Cruces University Hospital, Osakidetza-Basque Health Service, Biocruces-Bizkaia Health Research Institute, Barakaldo, SpainDepartment of Neurology, Cruces University Hospital, Osakidetza-Basque Health Service, Biocruces-Bizkaia Health Research Institute, Barakaldo, SpainDepartment of Neurology, Cruces University Hospital, Osakidetza-Basque Health Service, Biocruces-Bizkaia Health Research Institute, Barakaldo, SpainDepartment of Neurology, Txagorritxu University Hospital, Osakidetza-Basque Health Service, Bioaraba Health Research Institute, Vitoria-Gasteiz, SpainDepartment of Neurology, Galdakao-Usansolo University Hospital, Osakidetza-Basque Health Service, Biocruces-Bizkaia Health Research Institute, Galdakao, Spain0Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain1Department of Immunology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Red Española de Esclerosis Múltiple (REEM), Madrid, Spain0Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain0Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain1Department of Immunology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Red Española de Esclerosis Múltiple (REEM), Madrid, Spain0Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, SpainInflammation & Biomarkers Group, Biocruces-Bizkaia Health Research Institute, Barakaldo, Spain2Department of Biochemistry and Molecular Biology, Universidad del País Vasco (UPV/EHU), Barrio Sarriena, Leioa, Spain3Ikerbasque, Basque Foundation for Science, Bilbao, SpainIntronic 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.https://www.frontiersin.org/articles/10.3389/fimmu.2021.816930/fullANKRD55IL6STsgp130multiple sclerosisautoimmune |
| spellingShingle | Jorge Mena Iraide Alloza Raquel Tulloch Navarro Ane Aldekoa Javier Díez García Ane Villanueva Etxebarria Ane Villanueva Etxebarria Ane Villanueva Etxebarria Cecilia Lindskog Alfredo Antigüedad Sabas Boyero María del Mar Mendibe-Bilbao Amaya Álvarez de Arcaya José Luis Sánchez Menoyo Luciana Midaglia Noelia Villarrubia Sunny Malhotra Xavier Montalban Luisa María Villar Manuel Comabella Koen Vandenbroeck Koen Vandenbroeck Koen Vandenbroeck Genomic Multiple Sclerosis Risk Variants Modulate the Expression of the ANKRD55–IL6ST Gene Region in Immature Dendritic Cells Frontiers in Immunology ANKRD55 IL6ST sgp130 multiple sclerosis autoimmune |
| title | Genomic Multiple Sclerosis Risk Variants Modulate the Expression of the ANKRD55–IL6ST Gene Region in Immature Dendritic Cells |
| title_full | Genomic Multiple Sclerosis Risk Variants Modulate the Expression of the ANKRD55–IL6ST Gene Region in Immature Dendritic Cells |
| title_fullStr | Genomic Multiple Sclerosis Risk Variants Modulate the Expression of the ANKRD55–IL6ST Gene Region in Immature Dendritic Cells |
| title_full_unstemmed | Genomic Multiple Sclerosis Risk Variants Modulate the Expression of the ANKRD55–IL6ST Gene Region in Immature Dendritic Cells |
| title_short | Genomic Multiple Sclerosis Risk Variants Modulate the Expression of the ANKRD55–IL6ST Gene Region in Immature Dendritic Cells |
| title_sort | genomic multiple sclerosis risk variants modulate the expression of the ankrd55 il6st gene region in immature dendritic cells |
| topic | ANKRD55 IL6ST sgp130 multiple sclerosis autoimmune |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.816930/full |
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