RUNX1 recruitment of GCN5 in keratinocytes upregulates ICOSLG and promotes T cell activation in the psoriasis microenvironment.

Psoriasis is an immune-mediated disorder whose recurrence is primarily driven by cutaneous-resident T cells. Cutaneous T cells produce high levels of pathogenic cytokines, which subsequently initiate and sustain hyperproliferation and aberrant inflammatory cascades in keratinocytes. However, how keratinocytes orchestrate the activities of the cutaneous T cells remains elusive. Herein, single-cell RNA-sequencing and multiplex immunohistochemistry staining revealed that psoriatic keratinocytes upregulated the expression of T cell co-stimulator inducible T cell co-stimulator ligand (ICOSLG) and RUNX1, which showed a positive correlation. Multiplex immunohistochemistry further proved that ICOSLG colocalized with ICOS on T cell surfaces within psoriasis lesions, indicating that the ICOSLG-ICOS signal mediated keratinocyte-dependent T cell activation in psoriatic inflammation. Mechanistic investigations showed that RUNX1 transcriptionally upregulated ICOSLG expression via recruiting GCN5 (general control non-derepressible 5) to ICOSLG promoter, and the GCN5 inhibitor butyrolactone 3 (MB-3) reduced ICOSLG expression in keratinocytes. In a mouse model of psoriasis, MB-3 treatment ameliorated imiquimod-induced psoriatic lesion and its recurrence by suppressing keratinocyte ICOSLG expression and subsequent T cell activation. Notably, our keratinocyte-specific GCN5 knockdown mouse model demonstrated that this genetic ablation impaired the therapeutic benefits of MB-3. Taken together, these findings uncover the molecular mechanism driving ICOSLG upregulation in keratinocytes. Our study supports that clinical evaluation of the GCN5 inhibitor MB-3 is warranted for patients with psoriasis with ICOSLG overexpression.