FRI0014 A PUTATIVE ROLE OF IGF-1R ON THE PATHOGENESIS OF GOUT THROUGH BINDING TO TRANSCRIPTION FACTORS
Authors: R. Liu, O. Gaal, V. Klück, T. Crisan, S. Fanucchi, M. Mhlanga, L. Joosten
Journal: Annals of the Rheumatic Diseases (2020)

Background: Recent studies showed that SNPs on IGF-1/IGF-1R were highly associated with hyperuricemia and gout [1,2]. 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 resorption and secretion of uric acid. However, we demonstrated that the increased activation of IGF1R could activate the mTOR pathway, leading to a higher inflammatory response upon pathogen stimulation [3]. This finding indicates that IGF-1/IGF1-R has a role in inflammation, which could results in gout. The IGF-1/IGF-1R pathway may have an overall influence on both urate transporters and inflammatory pathways. it was shown that IGF-1R was not only expressed on the cell surface, but could also internalize into the nucleus and recruit RNA polymerase, regulating the expression of other transcription factors[4]. These transcription factors have been shown to regulate inflammation and have been predicted to bind promoter regions of urate transporters [5] Objectives: To unveil how the IGF-1/IGF1-R associates with hyperuricemia and gout by studying the IGF-1R SNP rs6598541. Methods: To assess the influence of the SNP to IGF1-R, the protein expression of IGF-1R on the cell surface was identified by flow cytometry in different genotypes. Additionally, we measured the in vitro immune response of PBMCs with different genotypes upon exposure to MSU and/or LPS. To estimate the overall influence of the SNP on the immune response, we analyzed the SNP’s function on transcription factors. Results: We observed an enhanced inflammatory response in the homozygous genotype with the risk alleles upon LPS and/or MSU stimulation, indicative of a higher risk for gout. However, the IGF-1R surface expression level was comparable between different genotypes. Furthermore, in epigenetic analysis, we found that rs6598541 located in an enhancer region, which is bound by c-FOS, c-JUN and other transcription factors. In recent years, c-FOS and c-JUN have been shown to regulate inflammatory responses. Conclusion: The risk allele of rs6598541 is associated with a higher inflammatory response, which might be the key factor for gout. Because of the location of the SNP, it might explain the function of IGF-1R in gout, and the pathogenesis might be modulated through transcription factors. According to the recent study, intracellular IGF-1R could act as a transcription factor regulating other transcription factors expression, like c-JUN. Additionally, c-JUN has been shown to regulate inflammatory responses. It is tempting to speculate that IGF-1R regulates transcription factors expression and leads to an overall immune responses, which influence the risk of 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]Mannino, G.C., et al., The polymorphism rs35767 at IGF1 locus is associated with serum urate levels. Sci Rep, 2018. 8 (1): p. 12255. [3]Bekkering, S., et al., Metabolic Induction of Trained Immunity through the Mevalonate Pathway. Cell, 2018. 172 (1-2): p. 135-146.e9. [4]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. [5]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. Disclosure of Interests: Ruiqi Liu: None declared, Orsi Gaal: None declared, Viola Klück: None declared, Tania Crisan: None declared, Stephanie Fanucchi: None declared, Musa Mhlanga: None declared, Leo Joosten Consultant of: SAB member of Olatec Therapeutics LLC