Targeting STING in Dendritic Cells Alleviates Psoriatic Inflammation

Psoriasis is a common chronic inflammatory skin disease primarily caused by abnormal activation of dendritic cells (DCs) and T cells, ultimately leading to increased cytokines such as interleukin (IL)-23 and IL-17A. The cGAS-STING pathway is known to play a key role in psoriatic inflammation, but the specific role of cGAS-STING signaling in DCs remains unclear.

This study was conducted by scholars from several renowned institutions, including Yueyang Hospital of Integrated Traditional Chinese and Western Medicine affiliated to Shanghai University of Traditional Chinese Medicine, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, and the First Affiliated Hospital of Sun Yat-sen University in Guangzhou. The research results were published in Cellular & Molecular Immunology in 2024 (DOI: 10.1038/s41423-024-01160-y). The main members of the research team include Xiaoying Sun, Liu Liu, Jiao Wang, and others, who conducted an in-depth investigation into the pathological mechanism of psoriasis.

Research Background

Psoriasis is a chronic autoimmune skin disease characterized by scaly plaques and erythema on the skin. Its pathogenesis is complex, involving interactions between multiple cell types and their associated inflammatory cytokines. DCs play a central role in the development of psoriasis, as they can recognize and present self-nucleic acids derived from cellular stress, thereby activating T cells and promoting their secretion of inflammatory factors such as IL-17, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α. These inflammatory factors further cause keratinocyte hyperproliferation and secretion of various inflammatory mediators, exacerbating the spread of psoriatic inflammation.

Research Objectives and Methods

This study aimed to reveal the role of cGAS-STING signaling in DCs and its specific mechanism in psoriatic inflammation, and to explore the therapeutic potential of alleviating psoriatic inflammation through targeting STING inhibitor C-176.

Research Process

1. Analysis of Clinical Samples and Mouse Models:

   • Analyzed skin samples from psoriasis patients and imiquimod (IMQ)-treated mice, finding that cGAS-STING signaling was significantly upregulated in psoriatic lesions.

2. Conditional STING Knockout Mouse Model:

   • Used conditional STING knockout transgenic mice (CD11c-Cre;STING^flox/flox) to study the role of STING in DCs activating IL-17 and IFN-γ secreting T cells.
   • Results showed that STING knockout led to reduced DC activation, decreased numbers of IL-17 secreting T cells (Th17) and Th1 cells, thereby alleviating IMQ-induced psoriatic inflammation in mice.

3. Therapeutic Potential of STING Inhibitor C-176:

   • Explored the therapeutic potential of STING inhibitor C-176, finding that it could reduce psoriatic inflammation and enhance the therapeutic effect of anti-IL-17A treatment.

Detailed Experimental Process

1. Analysis of Clinical Samples and Mouse Skin Samples:

   • Conducted mRNA expression analysis on 8 pairs of matched psoriatic lesions and non-lesional samples, finding that STING and cGAS were significantly upregulated in psoriatic lesions.
   • PASI scores (Psoriasis Area and Severity Index) showed strong correlation with STING or cGAS expression levels.

2. Establishment and Experiments with Conditional STING Knockout Mouse Model:

   • Generated transgenic mice with DC-specific STING knockout by crossing STING^flox/flox mice with CD11c-Cre mice.
   • Results showed that compared to wild-type mice, STING knockout mice exhibited reduced ear swelling, decreased epidermal thickness, inhibited epidermal hyperplasia, and alleviated psoriatic inflammation.

3. Application of STING Inhibitor C-176:

   • Administered C-176 via intraperitoneal injection to IMQ-induced psoriatic mice, observing a reduction in disease phenotype, including decreased ear swelling and epidermal thickness.

Main Research Conclusions and Value

The research results indicate that cGAS-STING signaling plays a crucial role in the development of psoriasis, and STING is a promising therapeutic target. The upregulation of STING signaling in DCs plays an important role in regulating the activation of IL-17 secreting T cells and Th1 cells in psoriatic lesions. Using the STING inhibitor C-176 can effectively inhibit DC function, reduce the expression of IL-17 and other inflammatory factors, thereby alleviating psoriatic inflammation.

This study reveals that targeting the STING signaling pathway may become a new strategy for treating psoriasis, and when combined with anti-IL-17A therapy, may provide a more effective treatment approach.

Research Highlights

1. In-depth revelation of the role of cGAS-STING signaling in psoriasis.
2. Demonstration of the specific role of STING in DCs using conditional STING knockout mouse models.
3. Confirmation of the potential of STING inhibitor C-176 in alleviating psoriatic inflammation, and demonstration of its synergistic effect with anti-IL-17A therapy.

This research not only deepens our understanding of the pathological mechanism of psoriasis but also provides a new perspective for precision treatment of psoriasis.