Journal
SCIENCE IMMUNOLOGY
Volume 6, Issue 64, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciimmunol.abg9012
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Funding
- Swiss National Science Foundation [310030_170320, 310030_188450, CRSII5_183478, PZ00P3_193330, 310030_189255]
- Swiss Personalized Health Network Driver project PRECISE
- Bern Center for Precision Medicine (BCPM)
- University Research Priority Program in Translational Cancer Research (URPP) at the University of Zurich
- UZH Forschungskredit [K-41302-11-01]
- Swiss National Science Foundation (SNF) [PZ00P3_193330, 310030_189255, 310030_170320] Funding Source: Swiss National Science Foundation (SNF)
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Psoriasis is a chronic inflammatory skin disorder caused by dysregulated cytokine signaling. Research shows that IL-12 signaling blocks the hyperproliferation of keratinocytes, maintains skin barrier integrity, and reduces disease-driving immune circuits. IL-23p19 inhibitors demonstrate superior efficacy in patients with psoriasis, potentially due to the unperceived role of IL-12 in maintaining skin epithelial cell homeostasis.
Psoriasis is a chronic inflammatory skin disorder underpinned by dysregulated cytokine signaling. Drugs neutralizing the common p40 subunit of interleukin-12 (IL-12) and IL-23 represented a therapeutic breakthrough; however, new drugs that block the IL-23p19 subunit and spare IL-12 are more effective, suggesting a regulatory function of IL-12. To pinpoint the cell type and underlying mechanism of IL-12-mediated immune regulation in psoriasis, we generated a conditional Il12rb2-knockout (KO)/reporter mouse strain. We detected Il12rb2 expression in T cells and a specific subset of interfollicular (IF) keratinocytes. Analysis of single-cell RNA-sequencing (scRNAseq) data from patients with psoriasis confirmed a similar expression pattern in the human skin. Deletion of Il12rb2 across the hematopoietic compartment did not alter the development of Aldara-induced psoriasiform inflammation. However, depletion of Il12rb2 in keratinocytes exacerbated disease development, phenocopying the Il12rb2 germline knockout. Protective IL-12 signaling blocked the hyperproliferation of keratinocytes, maintained skin barrier integrity, and diminished disease-driving IL-23/type 3 immune circuits. In line, specific IL-23p19 blockade led to a more profound reduction of psoriatic keratinocyte expression signatures in the skin of patients with psoriasis than combined IL-12/IL-23 inhibition. Collectively, we provide a potential explanation for the superior efficacy of IL-23p19 inhibitors in psoriasis and describe an unperceived role of IL-12 in maintaining skin epithelial cell homeostasis.
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