2. Academic Validation
  3. NLRP10 maintains epidermal homeostasis by promoting keratinocyte survival and P63-dependent differentiation and barrier function

NLRP10 maintains epidermal homeostasis by promoting keratinocyte survival and P63-dependent differentiation and barrier function

  • Cell Death Dis. 2024 Oct 18;15(10):759. doi: 10.1038/s41419-024-07146-y.
Yeonhee Cho 1,  Zhongzheng Cao 1 2,  Xin Luo 3,  Jennifer J Tian 4,  Renee R Hukkanen 5,  Rajaa Hussien 4,  Belinda Cancilla 4,  Priyanka Chowdhury 1,  Fei Li 6,  Shining Ma 3,  Edward L LaGory 7,  Mark Schroeder 7,  Amanda Dusenberry 8,  Leslie Marshall 8,  Jenn Hawkins 8,  Menno van Lookeren Campagne 1,  Yi Zhou 9
Affiliations

Affiliations

  • 1 Inflammation Research, Amgen Inc., South San Francisco, CA, USA.
  • 2 Amgen R&D Postdoctoral Fellows Program, South San Francisco, CA, USA.
  • 3 Center for Research Acceleration by Digital Innovation, Amgen Inc., South San Francisco, CA, USA.
  • 4 Translational Safety & Bioanalytical Sciences, Amgen Inc., South San Francisco, CA, USA.
  • 5 Translational Safety & Bioanalytical Sciences, Amgen Inc, Cambridge, MA, USA.
  • 6 Structural Biology, Amgen Inc., South San Francisco, CA, USA.
  • 7 Pharmacokinetics and Drug Metabolism, Amgen Inc., South San Francisco, CA, USA.
  • 8 Clinical Biomarkers, Amgen Inc, Thousand Oaks, CA, USA.
  • 9 Inflammation Research, Amgen Inc., South San Francisco, CA, USA. yzhou04@amgen.com.
PMID: 39424623 DOI: 10.1038/s41419-024-07146-y
Abstract

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 therapeutics for AD, there is still a large unmet medical need for disease management due to the complex and multifactorial nature of AD. Recent genome-wide association studies (GWAS) have identified NLRP10 as a susceptible gene for AD but the physiological role of NLRP10 in skin homeostasis and AD remains unknown. Here we show that NLRP10 is downregulated in AD skin samples. Using an air-lift human skin equivalent culture, we demonstrate that NLRP10 promotes keratinocyte survival and is required for epidermal differentiation and barrier function. Mechanistically, NLRP10 limits cell death by preventing the recruitment of Caspase-8 to the death inducing signaling complex (DISC) and by 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. 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.

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