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

系统性青少年特发性关节炎（Systemic juvenile idiopathic arthritis, sJIA）是一种严重的儿童关节炎，其特征是高尖峰热、皮疹、淋巴结病和关节炎的发作。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，导致疾病的发生和进展。sJIA炎症的特征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，DAMPs）以及白细胞介素1家族的细胞因子，即IL-1b和IL-18。在诊断后，sJIA患者经常接受类固醇或靶向IL-1b的治疗，但这些治疗的成功目前是不可预测的。无论成功的治疗管理，sJIA患者都有建立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。今天，目前对导致MAS的机制过程的理解表明IL-18的重要作用。重要的是，我们最近发现了主要在病毒防御过程中产生的1型干扰素，可以严格调节人类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的表达调节中的根本差异。虽然IFNa/b信号传导抑制IL-1b的表达和信号传导，但我们证明它促进IL-18的产生。事实上，这种相互作用对于平衡抗菌和抗病毒免疫至关重要，因为IFNa/b抵消IL-1的表达和信号传导，但控制炎症单核细胞的募集和IL-18的表达。反过来，IL-1信号可以限制IFNa/b的表达。在目前的项目中，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)研究抗il -1治疗（sJIA的标准治疗）是否实际上会破坏IL-1b-T1IFN的拮抗调节，从而可能导致IL-18过度表达，从而可能导致过度炎症和MAS。总的来说，本文产生的数据将增加我们对炎症环境如何与特异性抗炎药物一起预先处理MAS的理解，以及监测sJIA患者的1型干扰素特征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IL-1治疗在其他方面非常成功的警告，在特定情况下（遗传易感性，感染触发的性质）实际上可能构成风险因素。

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.