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Identification of disease susceptibility regions on chromosome 17 in a spondyloarthritis mouse modelIrving, Jeofferey-Ann 28 February 2024 (has links)
BACKGROUND: Spondyloarthritis is a subset of inflammatory rheumatic diseases that includes ankylosing spondyloarthritis, psoriatic arthritis, undifferentiated spondyloarthritis, and arthritis related to inflammatory bowel. The IL-23 cytokine has been implicated in the pathogenesis of spondyloarthritis. B10.RIII mice hydrodynamically injected with IL-23 minicircle overexpress the IL-23 cytokine, which leads to the development of spondyloarthritis-like disease. It is important to note that B10.RIII is a major histocompatibility complex (MHC) congenic mouse strain that is susceptible to autoimmune and autoinflammatory diseases where the background strain, C57BL/10 (B10), or the MHC donor strain, RIIIS/J, is resistant. For instance, the B10.RIII strain of mice is susceptible to IL-23-induced arthritis, while the B10 background strain is not. Large contaminating RIII-derived regions outside of the selected congenic interval on chromosome 17 were identified on chromosomes 10, 14, 15, and 17. Genetic variations in these intervals may contribute to the susceptibility of the B10.RIII mice to arthritis induced by IL-23 minicircle.
OBJECTIVE: This study aimed to interrogate the arthritis phenotype after IL-23 minicircle injection in Chr17 subcongenic B10.RIII mice. In addition, chromosome 17 RIII-derived Ilrun gene and its role in regulating the Interferon signaling pathway between the B10.RIII and B10 mice were investigated.
METHOD: Chromosome 17 subcongenic mice were generated by crossing B10.RIII mice with B10 mice and backcrossing the offspring to the B10.RIII mice. Offspring heterozygous b/r for the Chr17 region were then intercrossed to generate B10.RIII mice that are identical to the B10.RIII mice, except at chromosome 17, where they had the genotypes Chr17b/b, Chr17b/r, or Chr17r/r. These mice were then hydrodynamically injected with IL-23 minicircle DNA, and disease development was monitored every other day for two weeks using two parameters: clinical arthritis score and paw swelling. Bone marrow-derived macrophages were differentiated in vitro from B10.RIII and B10 mice. Cells were stimulated with TLR agonists (Pam3CSK4, Poly (I:C), LPS) that induce either the Ilrun-regulated Interferon signaling pathway or the NF-kB signaling pathway. Gene expression changes of NF-kB and Interferon-induced genes were measured using real-time quantitative PCR. TNF protein concentration in the supernatant was measured by ELISA.
RESULTS: Upon IL-23 minicircle injection, Chr17r/r and Chr17b/r B10.RIII mice developed arthritis while Chr17b/b B10.RIII mice did not. In addition, the disease severity increased with the number of r alleles as the Chr17r/r B10.RIII mice had a higher clinical score and paw swelling when compared to the heterozygote Chr17b/r mice. Gene expression analysis of NF-kB and Interferon response genes revealed that there was no difference in the induction of NF-kB and Interferon response genes in bone marrow-derived macrophages from B10.RIII and B10 mice. In addition, there was also no difference in the induction of the Ilrun gene in bone marrow-derived macrophages from B10.RIII and B10 mice.
CONCLUSION: The B10.RIII(71NS)/Sn strain contains three major RIII/WySn-derived regions outside of the congenic MHC region. The chromosome 17 cluster appears to play a role in susceptibility to IL-23 minicircle-induced arthritis. In vitro studies with bone marrow-derived macrophages failed to show functional differences in Ilrun between the B10.RIII and B10 mice. Future studies will interrogate chromosome 17 RIII-derived regions in arthritis development in more detail and investigate the role of Ilrun in immune responses using Ilrun knock-out mice. / 2025-02-28T00:00:00Z
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