Department of Dermatology, Fujita Health University School of Medicine, Toyoake, Japan.
Department of Dermatology, Nihon University School of Medicine, Tokyo, Japan.
J Eur Acad Dermatol Venereol. 2024 Oct;38(10):1910-1925. doi: 10.1111/jdv.19935. Epub 2024 May 23.
The interleukin (IL)-1 superfamily upregulates immune responses and maintains homeostasis between the innate and adaptive immune systems. Within the IL-1 superfamily, IL-36 plays a pivotal role in both innate and adaptive immune responses. Of the four IL-36 isoforms, three have agonist activity (IL-36α, IL-36β, IL-36γ) and the fourth has antagonist activity (IL-36 receptor antagonist [IL-36Ra]). All IL-36 isoforms bind to the IL-36 receptor (IL-36R). Binding of IL-36α/β/γ to the IL-36R recruits the IL-1 receptor accessory protein (IL-1RAcP) and activates downstream signalling pathways mediated by nuclear transcription factor kappa B and mitogen-activated protein kinase signalling pathways. Antagonist binding of IL-36Ra to IL-36R inhibits recruitment of IL-1RAcP, blocking downstream signalling pathways. Changes in the balance within the IL-36 cytokine family can lead to uncontrolled inflammatory responses throughout the body. As such, IL-36 has been implicated in numerous inflammatory diseases, notably a type of pustular psoriasis called generalized pustular psoriasis (GPP), a chronic, rare, potentially life-threatening, multisystemic skin disease characterised by recurrent fever and extensive sterile pustules. In GPP, IL-36 is central to disease pathogenesis, and the prevention of IL-36-mediated signalling can improve clinical outcomes. In this review, we summarize the literature describing the biological functions of the IL-36 pathway. We also consider the evidence for uncontrolled activation of the IL-36 pathway in a wide range of skin (e.g., plaque psoriasis, pustular psoriasis, hidradenitis suppurativa, acne, Netherton syndrome, atopic dermatitis and pyoderma gangrenosum), lung (e.g., idiopathic pulmonary fibrosis), gut (e.g., intestinal fibrosis, inflammatory bowel disease and Hirschsprung's disease), kidney (e.g., renal tubulointerstitial lesions) and infectious diseases caused by a variety of pathogens (e.g., COVID-19; Mycobacterium tuberculosis, Pseudomonas aeruginosa, Streptococcus pneumoniae infections), as well as in cancer. We also consider how targeting the IL-36 signalling pathway could be used in treating inflammatory disease states.
白细胞介素 (IL)-1 超家族上调免疫反应并维持先天免疫系统和适应性免疫系统之间的平衡。在 IL-1 超家族中，IL-36 在先天和适应性免疫反应中都发挥着关键作用。在四种 IL-36 同种型中，三种具有激动剂活性（IL-36α、IL-36β、IL-36γ），而第四种具有拮抗剂活性（IL-36 受体拮抗剂 [IL-36Ra]）。所有 IL-36 同种型都与 IL-36 受体 (IL-36R) 结合。IL-36α/β/γ 与 IL-36R 的结合招募白细胞介素 1 受体辅助蛋白 (IL-1RAcP)，并激活核转录因子 κB 和丝裂原激活蛋白激酶信号通路介导的下游信号通路。IL-36Ra 与 IL-36R 的拮抗剂结合抑制 IL-1RAcP 的募集，阻断下游信号通路。IL-36 细胞因子家族内平衡的变化可导致全身不受控制的炎症反应。因此，IL-36 与许多炎症性疾病有关，尤其是一种称为泛发性脓疱型银屑病 (GPP) 的脓疱型银屑病，这是一种慢性、罕见、潜在危及生命的多系统皮肤疾病，其特征是反复发热和广泛的无菌脓疱。在 GPP 中，IL-36 是疾病发病机制的核心，抑制 IL-36 介导的信号传导可以改善临床结局。在这篇综述中，我们总结了描述 IL-36 途径生物学功能的文献。我们还考虑了在广泛的皮肤（例如斑块型银屑病、脓疱型银屑病、化脓性汗腺炎、痤疮、 Netherton 综合征、特应性皮炎和坏疽性脓皮病）、肺部（例如特发性肺纤维化）、肠道（例如肠纤维化、炎症性肠病和先天性巨结肠）、肾脏（例如肾小管间质病变）和由多种病原体引起的传染病（例如 COVID-19；结核分枝杆菌、铜绿假单胞菌、肺炎链球菌感染）以及癌症中，IL-36 途径不受控制激活的证据。我们还考虑了如何靶向 IL-36 信号通路来治疗炎症性疾病状态。
