R. Liu 1, O. Gaal 3, V. Klück 1, T. O. Crișan 3, S. Fanucchi 4, M. Mhlanga 4, L. Joosten 1, 2, 3
1. Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands 2. Departement of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands 3. Department of Medical Genetics, “Luliu Hatieganu” University of Medicine And Pharmacy, Cluj Napoca, Romania. 4. Gene Expression and Biophysics Group, Division of Chemical, Systems and Synthetic Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
Background: Recent studies showed that genetic variation at the IGF1R locus is associated to hyperuricemia and gout . It was shown that the IGF-1/IGF-1R signaling pathway played a role in regulating the serum urate level. By modulating the uric acid transporters, IGF-1/IGF-1R influenced the reabsorption and secretion of uric acid. Moreover, we demonstrated that the increased activation of IGF-1R could activate the mTOR pathway, leading to a higher inflammatory response upon pathogen stimulation . This finding indicates that IGF-1/IGF1-R has a role in inflammation, which could be relevant for gout, in addition to the influence on urate transport. Recently, it was shown that IGF-1R is not only expressed on the cell surface,but is also internalized into the nucleus where it recruits RNA polymerase, regulating the expression of other transcription factors . These transcription factors have been shown to regulate inflammation and have been predicted to bind promoter regions of urate transporters .
Aim: To unveil how the IGF-1/IGF1-R pathway associates with gout by studying the IGF1R SNP rs6598541.
Methods: To assess the influence of the SNP to IGF-1R, the protein expression of IGF-1R on the cell surface of monocytes was identified by flow cytometry in different genotypes. Additionally, we measured the in vitro immune response of PBMCs with different genotypes upon exposure to LPS with or without MSU. To further explore the mechanism by which IGF-1R influences inflammation , we analyzed the SNP’s function on transcription factors.
Result: We observed an enhanced inflammatory response in the homozygous genotype with the risk alleles upon stimulation, indicative of a higher inflammatory cytokine production capacity. However, the IGF-1R surface expression level was the same between different genotypes. Furthermore, in epigenetic analysis, we found that rs6598541 is located in an enhancer region, which is bound by c-FOS, c-JUN and other transcription factors.
Discussion: The IGFR rs6598541 risk allele is associated with a higher inflammatory response. One underlying mechanism might be that the location of the SNP in the enhancer region affects the binding of transcription factors in this region, leading to different expression of inflammatory genes. A second hypothesis is that IGF-1R could act as a transcription factor itself, thereby regulating other transcription factor expression, including c-JUN which is known to regulate inflammatory responses [3, 4]. Both mechanisms could contribute to enhanced inflammation and therefore influence the risk of gout. Further exploring IGF-1R induced epigenetic changes will possibly provide novel treatment targets for gout.
References: 1. Kottgen A., et al., Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet, 2013. 45(2): p. 145-54. 2. Bekkering S., et al., Metabolic Induction of Trained Immunity through the Mevalonate Pathway. Cell, 2018. 172(1-2): p. 135-146.e9. 3. Aleksic T., et al., Nuclear IGF1R Interacts with Regulatory Regions of Chromatin to Promote RNA Polymerase II Recruitment and Gene Expression Associated with Advanced Tumor Stage. Cancer Res, 2018. 78(13): p. 3497-3509. 4. Granet C., W. Maslinski, and P. Miossec, Increased AP-1 and NF-kappaB activation and recruitment with the combination of the proinflammatory cytokines IL-1beta, tumor necrosis factor alpha and IL-17 in rheumatoid synoviocytes. Arthritis Res Ther, 2004. 6(3): p. R190-8.