Persistent Release of IL-1s from Skin Is Associated with Systemic Cardio-Vascular Disease, Emaciation and Systemic Amyloidosis: The Potential of Anti-IL-1 Therapy for Systemic Inflammatory Diseases

The skin is an immune organ that contains innate and acquired immune systems and thus is able to respond to exogenous stimuli producing large amount of proinflammatory cytokines including IL-1 and IL-1 family members. The role of the epidermal IL-1 is not limited to initiation of local inflammatory responses, but also to induction of systemic inflammation. However, association of persistent release of IL-1 family members from severe skin inflammatory diseases such as psoriasis, epidermolysis bullosa, atopic dermatitis, blistering diseases and desmoglein-1 deficiency syndrome with diseases in systemic organs have not been so far assessed. Here, we showed the occurrence of severe systemic cardiovascular diseases and metabolic abnormalities including aberrant vascular wall remodeling with aortic stenosis, cardiomegaly, impaired limb and tail circulation, fatty tissue loss and systemic amyloid deposition in multiple organs with liver and kidney dysfunction in mouse models with severe dermatitis caused by persistent release of IL-1s from the skin. These morbid conditions were ameliorated by simultaneous administration of anti-IL-1α and IL-1β antibodies. These findings may explain the morbid association of arteriosclerosis, heart involvement, amyloidosis and cachexia in severe systemic skin diseases and systemic autoinflammatory diseases, and support the value of anti-IL-1 therapy for systemic inflammatory diseases.皮肤作为一类免疫器官（immune organ），兼具先天免疫与适应性免疫系统，可对外源性刺激（exogenous stimuli）作出应答，产生包括白介素-1（IL-1）及白介素-1家族成员在内的大量促炎细胞因子（proinflammatory cytokines）。表皮白介素-1（epidermal IL-1）的作用不仅局限于启动局部炎症反应，还可诱导全身性炎症。然而，银屑病（psoriasis）、大疱性表皮松解症（epidermolysis bullosa）、特应性皮炎（atopic dermatitis）、水疱性疾病及桥粒芯糖蛋白-1（desmoglein-1）缺乏综合征等重症皮肤炎症性疾病中，白介素-1家族成员持续释放与全身器官病变的关联，迄今尚未得到评估。本研究在因皮肤持续释放白介素-1类物质引发重症皮炎的小鼠模型（mouse model）中，观察到严重全身性心血管疾病与代谢异常，包括血管壁异常重塑、主动脉瓣狭窄（aortic stenosis）、心脏肥大（cardiomegaly）、肢体与尾部循环障碍、脂肪组织丢失，以及多器官系统性淀粉样蛋白沉积（systemic amyloid deposition）并伴随肝肾功能异常。联合给予抗IL-1α与抗IL-1β抗体可改善上述病理状态。本研究结果或可阐释重症系统性皮肤病及全身性自身炎症性疾病中，动脉硬化（arteriosclerosis）、心脏受累、淀粉样变性（amyloidosis）与恶病质（cachexia）的病理关联，并支持抗IL-1治疗用于全身性炎症性疾病的临床价值。