IL-12 regulates type 3 immunity through interfollicular keratinocytes in psoriasiform inflammation

Sci Immunol. 2021 Oct 22;6(64):eabg9012. doi: 10.1126/sciimmunol.abg9012. Epub 2021 Oct 22.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Inflammation / immunology*
  • Interleukin-12 / genetics
  • Interleukin-12 / immunology*
  • Interleukin-23 / immunology*
  • Keratinocytes / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Psoriasis / immunology*
  • Receptors, Interleukin-12 / immunology*

Substances

  • Il12rb2 protein, mouse
  • Interleukin-23
  • Receptors, Interleukin-12
  • Interleukin-12