Poster Presentation Australasian Society for Dermatology Research Annual Scientific Meeting 2024

Epithelial and myeloid cell-specific STING signalling differentially regulate chronic inflammatory skin disease (#79)

Seen-Ling Sim 1 , Peter Murphy 1 , Erin McMeniman 2 , Snehlata Kumari 1
  1. The University of Queensland Frazer Institute, Woolloongabba, Queensland, Australia
  2. PAH Dermatology Department, Queensland Metro South Health, Woolloongabba, Queensland, Australia

Epithelial-immune cell interaction is crucial to maintain skin homeostasis. We have previously shown that dysregulation of Nuclear Factor-kappa B (NF-kB), and cell death signalling in epithelial cells triggered immune cell-mediated inflammation in the skin. However, the underlying mechanisms of their upstream regulators during chronic inflammatory skin diseases such as Psoriasis and Hidradenitis suppurative (HS) are poorly understood.

Cyclic GMP–AMP synthase (cGAS)–Stimulator of Interferon Genes (STING) pathway regulates NF-kB and cell death. We performed RNA sequencing on the epidermis from the lesional (LS) and non-lesional (NLS) skin of Hidradenitis Suppurativa patients and identified specific gene signatures of the STING and NF-kB pathways. To understand the cell-type-specific roles of STING, we generated epithelial-cell-specific (using K14Cre, hereafter named STINGE-KO) and macrophage-specific (using Cx3cr1Cre, hereafter named STINGM-KO) knock-out mice. We challenged these mice with imiquimod, a globally used preclinical murine model of skin inflammation, and using high dimensional 20-color flow cytometry, qPCR, and microscopy, analysed the effect of cell-type-specific sting deficiency on innate and adaptive immune cell recruitment, epidermal hyperproliferation, and regulation of proinflammatory cytokines and chemokines.  

Our results showed that macrophage-specific Sting regulates the accumulation of Epcam-CD3-CD45+CD11b+Ly6G+ neutrophils in the skin,  whereas keratinocyte-specific Sting regulates the development of inflammatory skin lesions. Specifically, preliminary results have shown amelioration of skin lesion development in the STINGE-KO mice, which was accompanied by reduced infiltration of innate and adaptive immune cells in the skin. Together, these results suggest a pro-inflammatory and pathogenic role of STING in keratinocytes in driving chronic skin disease.

These results highlight the cell-type-specific unique role of Sting in coordinating epithelial and immune homeostasis, dysregulation of which initiates and sustains chronic inflammatory skin diseases. This knowledge gain is crucial for developing specific and effective therapeutic approaches to skin diseases like Psoriasis and HS.