Dermal adipogenesis protects against neutrophilic skin inflammation

Abstract The skin’s immune response to danger signals involves rapid recruitment of neutrophils, but their excessive accumulation leads to inflammatory skin diseases, such as psoriasis, and how skin resident cells tolerate neutrophilic inflammation is poorly understood. Dermal white adipose tissue (dWAT) is an emerging component of the skin's immune barrier, but its role in controlling skin inflammation remains under-studied. Here, using an imiquimod-induced psoriasis mouse model, we observed a dynamic coupling between dermal adipogenesis, neutrophil infiltration and regression. During the early inflammatory phase, dWAT repopulates with PDGFRA+ preadipocytes that secrete CXCL1 and SAA3, attracting and activating CXCR2+ neutrophils. These neutrophils further activate preadipocytes through IL1β-IL1R signaling, establishing a self-sustaining inflammatory loop. Prolonged activation of pAds triggers PPARγ-dependent adipogenesis, leading to the formation of early adipocytes that secrete lipids exerting potent anti-inflammatory activity against myeloid cells, thereby aiding in inflammation resolution. Inhibition of adipogenesis, via targeted inhibition of PPARγ, through either pharmacological or genetic approaches, disrupts the formation of early adipocytes and prevents neutrophil regression and inflammation resolution. Analysis of human psoriatic cells identified a dFB subpopulation enriched with preadipocyte, IL1-pathway, and inflammatory gene signatures. Furthermore, transcriptomic analyses revealed a negative correlation between neutrophil-related inflammatory response with dermal adipogenesis response in generalized pustular psoriasis. Together, this study highlights the distinct roles of adipogenic fibroblasts and early adipocytes in initiating and resolving skin inflammation and suggests that promoting the differentiation of proinflammatory fibroblasts into anti-inflammatory early adipocytes could open avenues for the treatment of neutrophil-related inflammatory skin diseases, such as psoriasis and ulcers.