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. 2024 Sep;33(9):e15180.
doi: 10.1111/exd.15180.

IL23R mutations associated with decreased risk of psoriasis lead to the differential expression of genes implicated in the disease

Shraddha S Rane  1   2 , Elan Shellard  1 , Antony Adamson  1 , Steve Eyre  1   2 , Richard B Warren  1   2   3
Affiliations

IL23R mutations associated with decreased risk of psoriasis lead to the differential expression of genes implicated in the disease

Shraddha S Rane et al. Exp Dermatol. 2024 Sep.

Abstract

Psoriasis is an incurable immune-mediated skin disease, affecting around 1%-3% of the population. Various lines of evidence implicate IL23 as being pivotal in disease. Genetic variants within the IL23 receptor (IL23R) increase the risk of developing psoriasis, and biologic therapies specifically targeting IL23 demonstrated high efficacy in treating disease. IL23 acts via the IL23R, signalling through the STAT3 pathway, mediating the cascade of events that ultimately results in the clinical presentation of psoriasis. Given the essential role of IL23R in disease, it is important to understand the impact of genetic variants on receptor function with respect to downstream gene regulation. Here we developed model systems in CD4+ (Jurkat) and CD8+ (MyLa) T cells to express either the wild type risk or mutant (R381Q) protective form of IL23R. After confirmation that the model system expressed the genes/proteins and had a differential effect on the phosphorylation of STAT3, we used RNAseq to explore differential gene regulation, in particular for genes implicated with risk to psoriasis, at a single time point for both cell types, and in a time course experiment for Jurkat CD4+ T cells. These experiments discovered differentially regulated genes in the cells expressing wild type and mutant IL23R, including HLA-B, SOCS1, RUNX3, CCR5, CXCR3, CCR9, KLF3, CD28, IRF, SOCS6, TNFAIP and ICAM5, that have been implicated in both the IL23 pathway and psoriasis. These genes have the potential to define a IL23/psoriasis pathway in disease, advancing our understanding of the biology behind the disease.

Keywords: IL23; IL23R; STAT3; phospho‐STAT3; protective allele; psoriasis; risk allele.

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References

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