TY - JOUR
T1 - Genomic Multiple Sclerosis Risk Variants Modulate the Expression of the ANKRD55–IL6ST Gene Region in Immature Dendritic Cells
AU - Mena, Jorge
AU - Alloza, Iraide
AU - Tulloch Navarro, Raquel
AU - Aldekoa, Ane
AU - Díez García, Javier
AU - Villanueva Etxebarria, Ane
AU - Lindskog, Cecilia
AU - Antigüedad, Alfredo
AU - Boyero, Sabas
AU - Mendibe-Bilbao, María del Mar
AU - Álvarez de Arcaya, Amaya
AU - Sánchez Menoyo, José Luis
AU - Midaglia, Luciana
AU - Villarrubia, Noelia
AU - Malhotra, Sunny
AU - Montalban, Xavier
AU - Villar, Luisa María
AU - Comabella, Manuel
AU - Vandenbroeck, Koen
N1 - Publisher Copyright:
Copyright © 2022 Mena, Alloza, Tulloch Navarro, Aldekoa, Díez García, Villanueva Etxebarria, Lindskog, Antigüedad, Boyero, Mendibe-Bilbao, Álvarez de Arcaya, Sánchez Menoyo, Midaglia, Villarrubia, Malhotra, Montalban, Villar, Comabella and Vandenbroeck.
PY - 2022/1/17
Y1 - 2022/1/17
N2 - 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.
AB - 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.
KW - ANKRD55
KW - IL6ST
KW - autoimmune
KW - multiple sclerosis
KW - sgp130
UR - http://www.scopus.com/inward/record.url?scp=85123857289&partnerID=8YFLogxK
U2 - https://doi.org/10.3389/fimmu.2021.816930
DO - https://doi.org/10.3389/fimmu.2021.816930
M3 - Article
C2 - 35111166
AN - SCOPUS:85123857289
SN - 1664-3224
VL - 12
SP - 1
EP - 17
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 816930
ER -