Keratinocyte interleukin-36 receptor expression orchestrates psoriasiform inflammation in mice

Abstract

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.

IL-36 signaling in keratinocytes controls early IL-23 production in psoriasis-like dermatitis

“…However, we observed that K14Cre mice, but not K5Cre mice, were partly resistant to Aldara-induced psoriasis-like dermatitis. This difference may explain the difference between our data and those observed by Hernandez-Santana et al (2020).…”

“…While we were submitting this manuscript, another study performed with comparable methodology than ours demonstrated a similar resistance to Aldara-induced psoriasis-like dermatitis in K14Cre × Il36r fl/fl (DK14) mice than in Il36r-deficient mice, which corroborates our results (Hernandez-Santana et al, 2020). However, they observed some differences compared with our study.…”

“…However, they observed some differences compared with our study. For instance, they found that acanthosis was prevented in DK14 mice compared with Il36r fl/fl mice after 6 d of treatment and a reduction in TCRγδ + Vγ4 + IL-17A-producing T cells in Aldara-treated ears at d4 (Hernandez-Santana et al, 2020). However, we observed that K14Cre mice, but not K5Cre mice, were partly resistant to Aldara-induced psoriasis-like dermatitis.…”

IL-1 Family Antagonists in Mouse and Human Skin Inflammation

“…IL-36Ra expression was increased in psoriatic skin in mouse models or patients ( 79 , 116 – 118 , 178 , 180 , 195 , 199 – 204 ). IL-36 signaling in keratinocytes is mandatory for the development of Aldara (5% IMQ)-induced psoriasis ( 79 , 205 ), suggesting that the observed increase in IL-36Ra is insufficient to counterbalance the effects of agonistic IL-36 cytokines. Indeed, Il1f5 is strongly induced in skin of Aldara (5% IMQ)-treated mice ( 79 , 195 ), and IL-36α- but not IL-36β- or IL-36γ-deficient mice are protected in this model ( 206 ).…”

“…Indeed, Il1f5 is strongly induced in skin of Aldara (5% IMQ)-treated mice ( 79 , 195 ), and IL-36α- but not IL-36β- or IL-36γ-deficient mice are protected in this model ( 206 ). Another hypothesis could be related to the important, IL-36-mediated, neutrophil infiltration in psoriatic skin ( 24 , 79 , 205 ). Indeed, the supernatant of PMA-treated neutrophils has been shown to induce cleavage of IL-36Ra into the inactive S4 form ( 196 ).…”