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

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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.