IRAK4 Inhibition Dampens Pathogenic Processes Driving Inflammatory Skin Diseases

To examine the effect of a selective IRAK4 inhibitor, GLPG2534, in human and mouse models on central mediators of immune-mediated inflammatory diseases, such as psoriasis and atopic dermatitis.

This study included human samples from healthy individuals as well as those with atopic dermatitis and psoriasis for a total of 18 participants. The mouse models were done in female mice ages 9 to 18 weeks.

The study was done using incrementally more complex mouse models and human derived tissue cultures. The first part of this study collected blood samples from mice after the administration of GLPG2534. Inhibition of serum IL-6 and TNF-α were measured using mass spectrometry. Subsequently, the effect of GLPG2534 on human keratinocytes, human dermal fibroblasts, T cells isolated from PBMCs, human neutrophils, and human prebasophilic leukemia cells was assessed. The effect of GLPG2534 on TNF-α on human samples with atopic dermatitis as well as in mouse models was measured. In another experiment looking at the effect of IRAK4 inhibition in a psoriasis-like mouse model, ear thickness and gene expression was measured after 4 independent experiments. Study arms included recombinant IL-23 or IMQ treated ears with subsequent administration of TYK2 inhibitor or GLPG2534 in the former and anti-IL-12/IL-23p40 antibody or GLPG2534 in the latter group. Additionally, the effect of GLPG2534 in an atopic dermatitis-like mouse model was assessed evaluating treatment with either dexamethasone or GLPG2534. Ear thickness, eosinophils, T cells, and gene microarray were measured. In a final experiment, selected gene expression in human donors with either atopic dermatitis or psoriasis were measured.

GLPG2534 was shown to be a potent and selective inhibitor of IRAK4 and exhibits dose dependent TNF-α inhibition. GLPG2534 was shown to have statistically significant reduction in IL-4, IL-17A, IFN-γ, IL-22, IL-1β, IL-6, MPO, and IL-5 but only weakly affected dermal fibroblasts. From a gene expression standpoint, GLPG2534 was linked to statistically significant reduction in S100A7, DEFB4A, LCE3A, and IL19 expression. In the mouse ear models, GLPG2534 was shown to decrease ear thickness in both the psoriasis-like and atopic dermatitis-like models. The atopic dermatitis-like model was also significant for decreased eosinophil density and expression of multiple genes including CXCL8, CXCL5, LCE3A, MCP1, IL23, and TNF. The psoriasis-like model showed a statistically significant increase in IL37 expression and decrease in IL23 expression.

GLPG2534 administration and subsequent IRAK4 inhibition decreases multiple markers prevalent in inflammatory skin disease.

Cytokine-targeted biologics in immune-mediated inflammatory diseases is a growing area of research. This study demonstrates the potential of IRAK4 inhibition as a therapeutic strategy in inflammatory diseases and further studies in human models need to be done. This work has the ability to significantly impact the lives of children with atopic dermatitis and further studies in children are needed.