Disturbance of the Interleukin 1 (IL-1)/type 1 interferon/IL-18 balance as possible driver of cytokine storm and cytopenia in Macrophage Activation Syndrome

白细胞介素 1 (IL-1)/1 型干扰素/IL-18 平衡紊乱可能是巨噬细胞激活综合征中细胞因子风暴和血细胞减少的驱动因素

• 批准号: 513855158
• 负责人: Privatdozent Dr. Christoph Kessel
• 金额: --
• 依托单位: Klinik für Rheumatologie und klinischen Immunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/513855158?language=en
• 关键词: Disturbance; Interleukin; IL; type; interferon

Systemic juvenile idiopathic arthritis (sJIA) is a severe form of childhood arthritis, that is characterized by episodes of high-spiking fever, rash, lymphadenopathy and arthritis. Many, yet unknown genetic determinants, likely in combination with still un-identified environmental factors contribute to disease onset and progression. Inflammation in sJIA is hallmarked by molecules released in course of cell stress or uncontrolled cell death (Damage associated pattern molecules, DAMPs) as well as cytokines of the interleukin 1 family, namely IL-1b and IL-18. Following diagnosis, sJIA patients are frequently treated with steroids or therapies targeting IL-1b but success of these treatments is currently unpredictable. Regardless of successful therapeutic mangment, sJIA patients are at the continous risk to establish Macrophage Activation Syndrome (MAS) a severe, potentially fatal complication of the disease. Full-blown MAS requiring intensive medical care affects approximately 10% of sJIA patients. Today, current understanding of the mechanistic processes leading to MAS suggest an important role for IL-18. Importantly we recently identified type 1 interferons, which are mainly produced in course of viral defense, to critically modulate human IL-18 expression. This fits the clinical experience of episodes of MAS to associate with viral infection. It also highlights a fundamental difference of type 1 interferons in expression-regulation of the otherwise highly related inflammatory cytokines IL-1 and IL-18. While IFNa/b signaling restrains IL-1b expression and signaling, we demonstrate that it promotes IL-18 production. In fact, this interplay is crucial for balancing anti-bacterial versus anti-viral immunity in that IFNa/b counteracts IL-1 expression and signaling, but controls recruitment of inflammatory monocytes and IL-18 expression. In turn, IL-1 signaling can limit IFNa/b expression. In the present project we now aim to a) understand the contribution of DAMP-signaling to type 1 interferon and IL-18 expression and b) investigate whether anti-IL-1 therapies, which are standard-of-care in sJIA, can in fact destabilize the IL-1b-T1IFN counter-regulation, which may than result in excessive IL-18 expression and thus can predispose for hyperinflammation and MAS. Collectively, the data generated herein will increase our understanding on how the inflammatory environment together with specific anti-inflammatory medication may pre-dispose for MAS and whether monitoring of type 1 interferon signatures in sJIA patients can support prediction of hyperinflammation. Our data may further help to identify a caveat of the otherwise highly successful IL-1 therapy, which in specific scenarios (genetic pre-disposition, nature of the infectious trigger) may in fact pose a risk factor.

系统性幼年特发性关节炎 (sJIA) 是一种严重的儿童关节炎，其特征是发作高烧、皮疹、淋巴结肿大和关节炎。许多未知的遗传决定因素可能与尚未确定的环境因素相结合，导致疾病的发作和进展。 sJIA 炎症的特点是细胞应激或不受控制的细胞死亡过程中释放的分子（损伤相关模式分子，DAMP）以及白细胞介素 1 家族的细胞因子，即 IL-1b 和 IL-18。诊断后，sJIA 患者经常接受类固醇或针对 IL-1b 的治疗，但这些治疗的成功目前尚无法预测。无论治疗管理如何成功，sJIA 患者仍面临着巨噬细胞激活综合征 (MAS) 的持续风险，这是一种严重的、可能致命的疾病并发症。大约 10% 的 sJIA 患者患有需要重症监护的全面 MAS。如今，目前对导致 MAS 的机械过程的理解表明 IL-18 发挥着重要作用。重要的是，我们最近鉴定了 1 型干扰素，其主要在病毒防御过程中产生，可严格调节人 IL-18 的表达。这符合 MAS 发作与病毒感染相关的临床经验。它还强调了 1 型干扰素在高度相关的炎症细胞因子 IL-1 和 IL-18 的表达调节方面的根本区别。虽然 IFNa/b 信号传导抑制 IL-1b 表达和信号传导，但我们证明它可以促进 IL-18 的产生。事实上，这种相互作用对于平衡抗菌与抗病毒免疫至关重要，因为 IFNa/b 会抵消 IL-1 表达和信号传导，但控制炎症单核细胞的募集和 IL-18 表达。反过来，IL-1 信号传导可以限制 IFNa/b 的表达。在本项目中，我们现在的目标是：a) 了解 DAMP 信号传导对 1 型干扰素和 IL-18 表达的贡献，b) 研究作为 sJIA 护理标准的抗 IL-1 疗法实际上是否会破坏 IL-1b-T1IFN 反调节的稳定性，从而可能导致 IL-18 表达过度，从而导致过度炎症和 MAS。总的来说，本文生成的数据将加深我们对炎症环境与特定抗炎药物如何诱发 MAS 的理解，以及对 sJIA 患者 1 型干扰素特征的监测是否可以支持过度炎症的预测。我们的数据可能进一步有助于确定其他非常成功的 IL-1 疗法的一个警告，在特定情况下（遗传易感性、感染触发因素的性质），该疗法实际上可能构成风险因素。