AUTHOR=Mena Jorge , Alloza Iraide , Tulloch Navarro Raquel , Aldekoa Ane , Díez García Javier , Villanueva Etxebarria Ane , Lindskog Cecilia , Antigüedad Alfredo , Boyero Sabas , Mendibe-Bilbao María del Mar , Álvarez de Arcaya Amaya , Sánchez Menoyo José Luis , Midaglia Luciana , Villarrubia Noelia , Malhotra Sunny , Montalban Xavier , Villar Luisa María , Comabella Manuel , Vandenbroeck Koen 

TITLE=Genomic Multiple Sclerosis Risk Variants Modulate the Expression of the ANKRD55–IL6ST Gene Region in Immature Dendritic Cells

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.816930

DOI=10.3389/fimmu.2021.816930

ISSN=1664-3224

ABSTRACT=<p>Intronic single-nucleotide polymorphisms (SNPs) in the <italic>ANKRD55</italic> 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 <italic>ANKRD55</italic> and the neighboring <italic>IL6ST</italic> (gp130) gene in CD4<sup>+</sup> 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 <italic>ANKRD55</italic> during differentiation in immature monocyte-derived dendritic cells (moDCs) in the presence of interleukin (IL)-4/granulocyte-macrophage colony-stimulating factor (GM-CSF). <italic>ANKRD55</italic> expression levels are further enhanced by retinoic acid agonist AM580 but downregulated following maturation with interferon (IFN)-γ and lipopolysaccharide (LPS). <italic>ANKRD55</italic> was detected in the nucleus of moDC in nuclear speckles. We also analyzed the adjacent <italic>IL6ST</italic>, <italic>IL31RA</italic>, and <italic>SLC38A9</italic> genes. Of note, in healthy controls, MS risk SNP genotype influenced <italic>ANKRD55</italic> and <italic>IL6ST</italic> expression in immature moDC in opposite directions to that in CD4<sup>+</sup> T cells. This effect was stronger for a partially correlated SNP, rs13186299, that is located, similar to the main MS risk SNPs, in an <italic>ANKRD55</italic> intron. Upon analysis in MS patients, the main GWAS MS risk SNP rs7731626 was associated with <italic>ANKRD55</italic> expression levels in CD4<sup>+</sup> T cells. MoDC-specific <italic>ANKRD55</italic> and <italic>IL6ST</italic> 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 <italic>ANKRD55</italic> expression in moDC and indicates monocyte-to-dendritic cell (Mo–DC) differentiation as a process potentially influenced by MS risk SNPs.</p>