Dermal adipogenesis protects against neutrophilic skin inflammation during psoriasis pathogenesis.

Abstract

The immune response of the skin to danger signals involves rapid recruitment of neutrophils, but their excessive accumulation leads to inflammatory skin diseases, such as psoriasis; however, the mechanisms governing their initiation and resolution are poorly understood. Here, we revealed a dynamic immunoregulatory role of dermal white adipose tissue (dWAT) in the progression and resolution of neutrophilic skin inflammation in an imiquimod-induced psoriasis mouse model. During inflammation onset, dWAT repopulates PDGFRApreadipocytes (pAds), which secrete CXCL1 and SAA3, attracting and activating CXCR2neutrophils. These neutrophils further activate pAds through the IL-1R-NFκB-C/EBPδ pathway, establishing a self-sustaining inflammatory loop. Paradoxically, prolonged IL-1β signaling triggers PPARγ-dependent adipogenesis, transitioning pAds into anti-inflammatory early adipocytes that resolve neutrophilic inflammation via lipid mediators. Inhibition of adipogenesis, via pharmacological or genetic inhibition of PPARγ, disrupts the formation of early adipocytes, prevents neutrophil regression, and exacerbates inflammation. Analysis of human psoriatic cells revealed a C/EBPδdermal fibroblast (dFB) subpopulation enriched with preadipocytes, the IL-1 pathway, and inflammatory gene signatures. Furthermore, transcriptomic analyses revealed a negative correlation between the neutrophil-related inflammatory response and the dermal lipogenesis response in generalized pustular psoriasis. Together, our findings reveal the dual role of dWAT: PDGFRA+ pAds initiate inflammation via CXCL1/IL-1β crosstalk with neutrophils, whereas PPARγ-driven adipogenesis resolves this process through lipid mediators. This work establishes dWAT as a critical immunomodulatory hub and proposes adipogenic reprogramming of proinflammatory fibroblasts or topical delivery of early adipocyte lipids as innovative therapies for neutrophil-driven skin diseases, such as psoriasis and ulcers.