S100A9 Drives the Chronification of Psoriasiform Inflammation by Inducing IL-23/Type 3 Immunity

Area of Science:

• Immunodermatology
• Molecular mechanisms of skin inflammation
• Chronic inflammatory diseases

Background:

• Psoriasis is a chronic inflammatory skin condition driven by the IL-23/type 3 immune response.
• The molecular basis for the persistence of psoriatic inflammation and lesions is not fully understood.

Purpose of the Study:

• To identify key molecular mechanisms contributing to the chronicity of psoriasis.
• To investigate the role of S100A9 in the pathogenesis of psoriatic skin inflammation.

Main Methods:

• Systematic analysis of human psoriatic skin transcriptomic datasets.
• Validation in human lesioned skin and preclinical psoriasiform inflammation models.
• Genetic ablation and pharmacologic inhibition of S100A9.
• Single-cell RNA sequencing of human psoriatic skin.
• Bone marrow chimeric mouse experiments.

Main Results:

• S100A9 was identified as a significantly upregulated gene in psoriatic skin.
• Genetic or pharmacologic inhibition of S100A9 reduced skin inflammation.
• Keratinocytes were identified as the primary source of S100A9.
• S100A9 induced IL-23 production by dendritic cells, promoting IL-23/type 3 immunity.
• A feedback loop was observed where IL-23/IL-17 signaling upregulated S100A9 in keratinocytes.

Conclusions:

• S100A9 plays a crucial role in the chronification of psoriasis.
• An autoregulatory circuit exists between keratinocyte-derived S100A9 and IL-23/type 3 immunity in psoriasiform inflammation.
• Targeting S100A9 may offer a therapeutic strategy for chronic psoriasis.