S1PR3-driven positive feedback loop sustains STAT3 activation and keratinocyte hyperproliferation in psoriasis

Area of Science:

• Dermatology
• Molecular Biology
• Immunology

Background:

• Psoriasis is a chronic inflammatory skin disease driven by keratinocyte hyperproliferation and inflammation.
• Persistent activation of signal transducer and activator of transcription 3 (STAT3) is implicated in psoriasis, but its sustaining mechanisms are unclear.

Purpose of the Study:

• To identify key regulators of STAT3 activation in psoriasis pathogenesis.
• To elucidate the molecular mechanisms linking sphingosine-1-phosphate receptor 3 (S1PR3) to STAT3 activation and psoriasis.
• To evaluate S1PR3 as a potential therapeutic target for psoriasis.

Main Methods:

• Analysis of S1PR3 expression in psoriatic lesions.
• Genetic (S1pr3 deletion) and pharmacological inhibition of S1PR3 in mouse models.
• Investigation of the S1PR3-Src-STAT3 signaling axis and STAT3 feedback loop.

Main Results:

• S1PR3 expression is elevated in psoriasis and correlates with disease severity.
• A novel S1PR3-Src-STAT3 signaling axis sustains STAT3 activation in keratinocytes.
• Activated STAT3 upregulates S1PR3, creating a positive feedback loop driving inflammation and hyperproliferation.
• S1PR3 inhibition significantly reduced psoriasis-like skin inflammation in mice.

Conclusions:

• S1PR3 is a critical regulator of psoriasis pathogenesis through a self-amplifying S1PR3-STAT3 feedback loop.
• Targeting S1PR3 offers a promising therapeutic strategy for psoriasis.
• Disrupting this feedback loop may benefit other chronic inflammatory diseases involving STAT3 activation.