Saturated fatty acids-induced neutrophil extracellular traps contribute to exacerbation and biologic therapy resistance in obesity-related psoriasis

Psoriasis patients with obesity tend to show a serious clinical manifestation and have poor responses to various biological agents in most cases. However, the mechanisms in obesity-exacerbated psoriasis remain enigmatic. In this study, we found that the abundance of systemic and localized cutaneous neutrophil extracellular traps (NETs) in obesity-induced aggravation of psoriasis was positively correlated with disease severity, and inhibition of NETs alleviated psoriatic dermatitis in obese mice. Mechanistically, we found that changes of fatty acid composition in obese subjects resulted in the deposit of saturated fatty acids (SFAs), which promoted the release of NETs via the TLR4-MD2/ROS signaling pathway. We further found that NETs potentiated IL-17 inflammation in obesity-exacerbated psoriasis, especially γδT17-mediated immune responses. Moreover, SFAs induced decreased response to anti-IL17A treatment in psoriasis-like mice, whereas inhibition of NETs improved the beneficial effects of anti-IL17A in psoriasis-like mice with lipid metabolism disorders. Our findings collectively suggest that SFAs-induced NETs play a critical role in the exacerbation of obesity-related psoriasis, and provide potential new strategies for the treatment of refractory psoriasis patients with lipid metabolism disorders clinically.