Keratinocyte interleukin-36 receptor expression orchestrates psoriasiform inflammation in mice

The IL-36 family cytokines have emerged as important mediators of dermal inflammation in psoriasis and have been reported to provide a proinflammatory stimulus to a variety of immune and stromal cell subsets in the inflamed skin. However, it remains to be determined which cell type, if any, in the skin plays a predominant role in mediating IL-36 cytokines instructive role in disease. Here, we demonstrate that targeted deletion of Il36r in keratinocytes results in similar levels of protection from psoriasiform inflammation observed in “global” Il36r-deficient mice. Mice with deficiency in IL-36 receptor expression on keratinocytes had significantly decreased expression, comparable with Il36r-deficient mice, of established mediators of psoriatic inflammation, including, IL-17a, IL-23, IL-22, and a loss of chemokine-induced neutrophil and IL-17A–expressing γδ T-cell subset infiltration to the inflamed skin. These data demonstrate that keratinocytes are the primary orchestrating cell in mediating the effects of IL-36–driven dermal inflammation in the imiquimod model of psoriasiform inflammation and shed new light on the cell-specific roles of IL-36 cytokines during psoriatic disease.