Loss-of-function mutations in IL36RN cause generalized pustular psoriasis (GPP), which is characterized by neutrophil-infiltrated lesions. Neutrophils are important during contact hypersensitivity in mice. However, it has never been determined whether interleukin-36 receptor antagonist (IL-36Ra) deficiency is an exacerbating factor in contact dermatitis. We examined whether a loss-of-function IL36RN mutation exacerbates contact dermatitis and evaluated the changes in contact dermatitis-related cytokines. Wild-type and Il36rn-/- mice were treated with 1-fluoro-2,4-dinitorobenzene (DNFB) and evaluated for ear thickness, histopathological features, numbers of infiltrated neutrophils, and numbers of CD4 + and CD8 + T cells. Furthermore, mRNA levels of contact dermatitis-related cytokines were measured by real-time polymerase chain reaction, and effects of TAK-242, a toll-like receptor 4 (TLR4) inhibitor, on the contact hypersensitivity (CHS) response were evaluated. We found that the ear thickness, cytokine expression, and neutrophil infiltration significantly increased in Il36rn-/- mice compared with that in wild-type mice. TAK-242 alleviated CHS and prevented neutrophil infiltration, cytokine expression, and ear thickening in Il36rn-/- mice. These data indicate that Il36rn-/- mutations are an exacerbating factor for CHS and that TAK-242 can reduce the inflammatory responses that are associated with the CHS response.

中文翻译：

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TAK-242可改善因IL-36受体拮抗剂缺乏而加剧的接触性皮炎。

IL36RN中的功能丧失突变会导致全身性脓疱型牛皮癣（GPP），其特征是嗜中性粒细胞浸润性病变。中性粒细胞在小鼠接触超敏反应中很重要。然而，从未确定白介素36受体拮抗剂（IL-36Ra）缺乏症是否是接触性皮炎的加剧因素。我们检查了功能丧失的IL36RN突变是否加剧了接触性皮炎，并评估了接触性皮炎相关细胞因子的变化。将野生型和Il36rn-/-小鼠用1-fluoro-2,4-dinitorobenzene（DNFB）处理，并评估其耳厚，组织病理学特征，浸润的中性粒细胞数量以及CD4 +和CD8 + T细胞数量。此外，通过实时聚合酶链反应测量接触性皮炎相关细胞因子的mRNA水平，评估了Toll样受体4（TLR4）抑制剂TAK-242对接触性超敏反应（CHS）反应的影响。我们发现与野生型小鼠相比，Il36rn-/-小鼠的耳厚，细胞因子表达和中性粒细胞浸润显着增加。TAK-242可减轻CHS并预防Il36rn-/-小鼠中的中性粒细胞浸润，细胞因子表达和耳朵增厚。这些数据表明Il36rn-/-突变是CHS的恶化因素，并且TAK-242可减少与CHS反应相关的炎性反应。与野生型小鼠相比，Il36rn-/-小鼠的中性粒细胞浸润和中性粒细胞浸润显着增加。TAK-242可减轻CHS并预防Il36rn-/-小鼠中的中性粒细胞浸润，细胞因子表达和耳朵增厚。这些数据表明Il36rn-/-突变是CHS的恶化因素，并且TAK-242可减少与CHS反应相关的炎性反应。与野生型小鼠相比，Il36rn-/-小鼠的中性粒细胞浸润和中性粒细胞浸润显着增加。TAK-242可减轻CHS并预防Il36rn-/-小鼠中的中性粒细胞浸润，细胞因子表达和耳朵增厚。这些数据表明Il36rn-/-突变是CHS的恶化因素，并且TAK-242可减少与CHS反应相关的炎性反应。