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

Abstract

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