Abstract
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.
Highlights
Psoriasis is a chronic recurrent inflammatory skin disease with a complex pathogenesis [1, 2]
We confirm that psoriatic neutrophils are activated and form neutrophil extracellular traps (NETs) in psoriasis patients compared to healthy controls. Using both in vivo and in vitro approaches, we demonstrate that neutrophils, through release of NETs, amplify skin inflammation through activation of IL-36 and tolllike receptor 4 (TLR4) signaling
We demonstrated that interleukin (IL)-17A, tumor necrosis factor (TNF)-α, high mobility group box-1 (HMGB1), and LCN2, all of which are elevated in psoriasis [4, 19, 32], were potent inducers of NETs formation, and comparable to induction by phorbol 12myristate 13-acetate (PMA), which was used as a positive control (Figure S1B)
Summary
Psoriasis is a chronic recurrent inflammatory skin disease with a complex pathogenesis [1, 2]. It is generally considered that the main pathogenic driver of psoriasis is an intricate interplay between infiltrated inflammatory cells and activated keratinocytes [3, 4]. While the roles of dendritic cells (DCs), T cells, and macrophages have been extensively investigated [5,6,7,8], the contribution of neutrophils, the most abundant leukocyte population of the immune system in humans, has remained unclear. Neutrophils play a crucial role in a wide variety of conditions, including infections, autoimmune, neoplastic, and chronic inflammatory diseases [9,10,11,12]. No studies have comprehensively addressed the role of neutrophils in psoriasis, but neutrophil involvement is suggested by the results from several clinical studies, in which selective depletion of granulocytes and monocytes by adsorptive apheresis led to marked improvement in psoriasis symptoms [13, 14]
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