ΔNp63 regulates IL-33 and IL-31 signaling in atopic dermatitis

Abstract

Atopic dermatitis (AD) is the most common inflammatory skin disease with no well-delineated cause or effective cure. Here we show that the p53 family member p63, specifically the ΔNp63, isoform has a key role in driving keratinocyte activation in AD. We find that overexpression of ΔNp63 in transgenic mouse epidermis results in a severe skin phenotype that shares many of the key clinical, histological and molecular features associated with human AD. This includes pruritus, epidermal hyperplasia, aberrant keratinocyte differentiation, enhanced expression of selected cytokines and chemokines and the infiltration of large numbers of inflammatory cells including type 2 T-helper cells – features that are highly representative of AD dermatopathology. We further demonstrate several of these mediators to be direct transcriptional targets of ΔNp63 in keratinocytes. Of particular significance are two p63 target genes, IL-31 and IL-33, both of which are key players in the signaling pathways implicated in AD. Importantly, we find these observations to be in good agreement with elevated levels of ΔNp63 in skin lesions of human patients with AD. Our studies reveal an important role for ΔNp63 in the pathogenesis of AD and offer new insights into its etiology and possible therapeutic targets.

Interleukin‐33 (IL‐33): A nuclear cytokine from the IL‐1 family

“…In the digestive tract, IL‐33 is expressed by epithelial cells from salivary glands, mucosal surface of the stomach and gastric glands (Figure C), both in humans and mice . In the skin, IL‐33 expression is constitutive in murine keratinocytes but inducible in human keratinocytes, particularly during atopic dermatitis where it may be regulated by p53 family member p63 (specifically ΔNp63) . In our studies, we consistently observed nuclear IL‐33 staining in human skin keratinocytes and epithelial cells of the stomach, but we noticed significant variability between different cells, different part of the tissues and different individuals, suggesting local regulation by environmental cues .…”

Potential role of TP63 in apical periodontitis development

“…TP63 also has an important role in the pathogenesis of atopic dermatitis, a chronic inflammatory skin disease (Rizzo et al . ). AP is also a chronic inflammatory disease of the periradicular tissues that is caused by microorganisms infecting the pulp tissues, therefore it can be hypothesized that TP63 likely plays a role in AP development.…”

“…Increased expression of TP63 was observed in epithelial cells and damaged parenchyma cells of lung after viral infections with H1N1 influenza virus (Kumar et al 2011, Zheng et al 2014, and in the olfactory epithelium during acute inflammatory response (Chen et al 2017). TP63 also has an important role in the pathogenesis of atopic dermatitis, a chronic inflammatory skin disease (Rizzo et al 2016). AP is also a chronic inflammatory disease of the periradicular tissues that is caused by microorganisms infecting the pulp tissues, therefore it can be hypothesized that TP63 likely plays a role in AP development.…”

Expression of IL-22 in the Skin Causes Th2-Biased Immunity, Epidermal Barrier Dysfunction, and Pruritus via Stimulating Epithelial Th2 Cytokines and the GRP Pathway

“…Skin-specific expression of IL-4, IL-13, TSLP, and IL-33 elicited pruritic AD-like dermatitis (16, 37–40). More recently, a study showed that transgenic expression of ΔNp63 resulted in keratinocyte activation and an AD-like phenotype (41). Several studies, including our own, have showed that chronic epicutaneous antigen exposure caused AD-like dermatitis and enhanced airway inflammation and airway obstruction after allergen inhalation challenge (21, 42).…”