Neutrophil extracellular traps are induced in a psoriasis model of interleukin-36 receptor antagonist-deficient mice.

Loss-of-function mutations in the interleukin (IL)-36 gene IL36RN are associated with psoriasis. The importance of neutrophil extracellular traps (NETs), web-like structures composed of neutrophil DNA, in the pathogenesis of psoriasis has been unclear. Here, we aimed to clarify the role of NET signaling in the deficiency of IL36 receptor antagonist (DITRA). We evaluated the severity of psoriasis-like lesions induced by imiquimod cream treatment in Il36rn−/− mice. The mRNA levels of psoriasis-related cytokines were measured via real-time reverse transcription polymerase chain reaction, and the effects of Cl-amidine, a peptidyl arginine deiminase 4 (PAD4) inhibitor, on psoriasis-like lesions were evaluated. PAD4 is a histone-modifying enzyme that is involved in NET formation. Psoriasis area and severity index scores, epidermal thickness, and infiltrated neutrophil counts were significantly increased in Il36rn−/− mice; NET formation was confirmed pathologically. Several cytokines and chemokines were upregulated in the skin lesions of Il36rn−/− mice and Cl-amidine treatment improved these psoriasis-like lesions. These results suggest that NET formation plays an important role in the pathology of psoriasis-like lesions in these mice and might represent a promising therapeutic target for DITRA.

白细胞介素（IL）-36基因IL36RN的功能缺失突变与银屑病相关。中性粒细胞胞外陷阱（NETs）是由中性粒细胞DNA组成的网状结构，其在银屑病发病机制中的重要性尚不清楚。在此，我们旨在阐明NET信号在IL36受体拮抗剂缺乏症（DITRA）中的作用。我们评估了咪喹莫特乳膏处理在Il36rn - / -小鼠中诱导的银屑病样皮损的严重程度。通过实时逆转录聚合酶链反应测量银屑病相关细胞因子的mRNA水平，并评估了肽基精氨酸脱亚胺酶4（PAD4）抑制剂Cl - 脒对银屑病样皮损的影响。PAD4是一种参与NET形成的组蛋白修饰酶。Il36rn - / -小鼠的银屑病面积和严重程度指数评分、表皮厚度以及浸润的中性粒细胞计数显著增加；NET形成在病理学上得到证实。几种细胞因子和趋化因子在Il36rn - / -小鼠的皮肤病变中上调，并且Cl - 脒治疗改善了这些银屑病样皮损。这些结果表明，NET形成在这些小鼠的银屑病样皮损的病理过程中起重要作用，并且可能是DITRA的一个有前景的治疗靶点。