Skin-localized sympathetic nerve–keratinocyte crosstalk fuels psoriatic inflammation via neutrophil recruitment

BACKGROUND: Psoriasis is a common immune-mediated inflammatory skin disease. The sympathetic nervous system (SNS), a complex network consisting of endocrine and local arms, holds a significant position in the modulation of immune response, while the exact function varies depending on the specific disease type, the type of cell involved, and the intricate architecture of the SNS. Therefore, this study aimed to elucidate the precise role of sympathetic signaling in psoriasis. METHODS: Using an imiquimod-induced psoriasis mouse model, we evaluated the in vivo effects of sympathetic signaling intervention through gross phenotype observation, histology, and flow cytometric analysis of inflammatory cell infiltrations. Human primary keratinocytes (KCs), isolated from donor foreskins from patients under undergoing urological surgery at the Department of Urology, Xijing Hospital, were employed to investigate the role and mechanism of sympathetic signaling in regulating C-X-C motif chemokine ligand 1 (CXCL1) production and neutrophil recruitment, utilizing Western blot analysis, immunofluorescence and transwell assays. RESULTS: In psoriatic mice, local denervation of skin sympathetic fibers resulted in markedly reduced erythema, scaling, and epidermal thickness compared to controls, while systemic denervation did not. Local denervation also reduced neutrophil infiltration in skin lesions. This reduction was associated with sympathetic signaling that upregulated CXCL1 expression in KCs without altering Keratin 1, Keratin 10, or interleukin (IL)-25 levels. The β2-adrenergic receptor (ADRB2) was highly expressed in psoriatic KCs. KCs treated with norepinephrine (NE) or ADRB2 agonist salbutamol increased cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation and CXCL1 expression, effects that were abolished by an ADRB2 antagonist. In mice, topical salbutamol increased local CXCL1, accelerated early neutrophil infiltration, and worsened subsequent erythema, scaling, and epidermal thickening. Conversely, topical ADRB2 antagonist or CREB inhibitor application decreased epidermal thickening, reduced CXCL1 expression, and lowered neutrophil infiltration. CONCLUSIONS: Activation of skin local sympathetic signaling in KCs induces CXCL1 production via the ADRB2-CREB pathway, which contributes to recruiting neutrophils to the skin lesions and fuels psoriatic inflammation.