PDF(Pubmed)
Abstract：
Plaque psoriasis is an autoinflammatory and autoimmune skin disease, affecting 1-3% of the population worldwide. Previously, high levels of IL-36 family cytokines were found in psoriatic skin lesions, thereby contributing to keratinocyte hyperproliferation and infiltration of immune cells such as neutrophils. While treatment with anti-IL36 receptor (IL36R) antibodies was recently approved for generalized pustular psoriasis (GPP), it remains unclear, if targeting the IL36R might also inhibit plaque psoriasis. Here we show that antibody-mediated inhibition of IL36R is sufficient to suppress imiquimod-induced psoriasis-like skin inflammation and represses the disease\'s development in a model that depends on IL-17A overexpression in the skin. Importantly, treatment with anti-IL36R antibodies inhibited skin inflammation and attenuated psoriasis-associated, systemic inflammation. This is possibly due to a widespread effect of IL36R inhibition, which not only suppresses pro-inflammatory gene expression in keratinocytes, but also the activation of other immune cells such as T-cells or dendritic cells. In conclusion, we propose that inhibition of the IL-36 signaling pathway might constitute an attractive, alternative approach for treating IL-17A-driven psoriasis and psoriasis-linked comorbidities.
摘要：
斑块型银屑病是一种自身炎症和自身免疫性皮肤病，影响全球1-3%的人口。以前,在银屑病皮损中发现高水平的IL-36家族细胞因子，从而有助于角质形成细胞过度增殖和免疫细胞如嗜中性粒细胞的浸润。虽然抗IL36受体（IL36R）抗体的治疗最近被批准用于全身性脓疱型银屑病（3GPP），目前还不清楚,如果靶向IL36R也可能抑制斑块状银屑病。在此，我们显示抗体介导的IL36R抑制足以抑制咪喹莫特诱导的银屑病样皮肤炎症，并在依赖于皮肤IL-17A过度表达的模型中抑制疾病的发展。重要的是,用抗IL36R抗体治疗可抑制皮肤炎症并减轻牛皮癣相关，全身性炎症。这可能是由于IL36R抑制的广泛作用，不仅抑制角质形成细胞中促炎基因的表达，但也激活其他免疫细胞，如T细胞或树突状细胞。总之,我们认为，抑制IL-36信号通路可能构成一个有吸引力的，治疗IL-17A驱动的银屑病和银屑病相关合并症的替代方法。
