NLRP10 Maintains Epidermal Homeostasis by Promoting Keratinocyte Survival and P63-Dependent Differentiation and Barrier Function

Atopic dermatitis (AD) is a common chronic inflammatory skin disorder characterized by disrupted epidermal barrier function and aberrant immune responses. Despite recent developments in new treatments for AD, there are still unmet needs for the disease management due to its complex and multifactorial nature. Recent genome-wide association studies (GWAS) have identified NLRP10 as an AD susceptible gene. However, the physiological role of NLRP10 in skin homeostasis and its relevance to AD are unknown. Here we show that NLRP10 promotes keratinocyte survival and facilitates epidermal differentiation and barrier function. Mechanistically, NLRP10 limits cell death by preventing the recruitment of caspase-8 onto the death inducing signaling complex and inhibiting its subsequent activation. NLRP10 also stabilizes p63, the master regulator of keratinocyte differentiation, to drive proper keratinocyte differentiation and to reinforce the barrier function. Importantly, NLRP10 is downregulated in AD skin samples. Our findings underscore NLRP10 as a key player in atopic dermatitis pathogenesis, highlighting NLRP10 as a potential target for therapeutic intervention to restore skin barrier function and homeostasis in AD. Overall design: mRNA sequencing of human skin equivalent cultures of NLRP-10 knockout (KO) and control wildtype (WT) primary normal human epidermis keratinocytes NHEKs.