Neutrophil Extracellular Traps Promote Inflammatory Responses in Psoriasis via Activating Epidermal TLR4/IL-36R Crosstalk

Frontiers in Immunology

Johann E. Gudjonsson¹  Shuai Shao²  Shengxian Shen²  Hongjiang Qiao²  Gang Wang²  Hui Fang²  Tianyu Cao²  Jieyu Zhang²  Caixia Li²  Tongmei Zhang²  Pei Qiao²  Bing Li²  Yuchen Zhuang²  Erle Dang²  Ke Xue² 

[1] Department of Dermatology, University of Michigan, Ann Arbor, MI, United States;Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China;

关键词: psoriasis;    neutrophil extracellular traps;    IL-36;    TLR4;    keratinocyte;   

DOI  :  10.3389/fimmu.2019.00746

来源: DOAJ

【 摘 要 】

Epidermal infiltration of neutrophils is a hallmark of psoriasis, where their activation leads to release of neutrophil extracellular traps (NETs). The contribution of NETs to psoriasis pathogenesis has been unclear, but here we demonstrate that NETs drive inflammatory responses in skin through activation of epidermal TLR4/IL-36R crosstalk. This activation is dependent upon NETs formation and integrity, as targeting NETs with DNase I or CI-amidine in vivo improves disease in the imiquimod (IMQ)-induced psoriasis-like mouse model, decreasing IL-17A, lipocalin2 (LCN2), and IL-36G expression. Proinflammatory activity of NETs, and LCN2 induction, is dependent upon activation of TLR4/IL-36R crosstalk and MyD88/nuclear factor-kappa B (NF-κB) down-stream signaling, but independent of TLR7 or TLR9. Notably, both TLR4 inhibition and LCN2 neutralization alleviate psoriasis-like inflammation and NETs formation in both the IMQ model and K14-VEGF transgenic mice. In summary, these results outline the mechanisms for the proinflammatory activity of NETs in skin and identify NETs/TLR4 as novel therapeutic targets in psoriasis.

【 授权许可】

Unknown