Abstract
Unchecked inflammation can result in severe diseases with high mortality, such as macrophage activation syndrome (MAS). MAS and associated cytokine storms have been observed in COVID-19 patients exhibiting systemic hyperinflammation. Interleukin-18 (IL-18), a proinflammatory cytokine belonging to the IL-1 family, is elevated in both MAS and COVID-19 patients, and its level is known to correlate with the severity of COVID-19 symptoms. IL-18 binds its specific receptor IL-1 receptor 5 (IL-1R5, also known as IL-18 receptor alpha chain), leading to the recruitment of the coreceptor, IL-1 receptor 7 (IL-1R7, also known as IL-18 receptor beta chain). This heterotrimeric complex then initiates downstream signaling, resulting in systemic and local inflammation. Here, we developed a novel humanized monoclonal anti-IL-1R7 antibody to specifically block the activity of IL-18 and its inflammatory signaling. We characterized the function of this antibody in human cell lines, in freshly obtained peripheral blood mononuclear cells (PBMCs) and in human whole blood cultures. We found that the anti-IL-1R7 antibody significantly suppressed IL-18-mediated NFκB activation, reduced IL-18-stimulated IFNγ and IL-6 production in human cell lines, and reduced IL-18-induced IFNγ, IL-6, and TNFα production in PBMCs. Moreover, the anti-IL-1R7 antibody significantly inhibited LPS- and Candida albicans–induced IFNγ production in PBMCs, as well as LPS-induced IFNγ production in whole blood cultures. Our data suggest that blocking IL-1R7 could represent a potential therapeutic strategy to specifically modulate IL-18 signaling and may warrant further investigation into its clinical potential for treating IL-18-mediated diseases, including MAS and COVID-19.
Highlights
18 forms a signaling complex by binding to the IL-1 receptor 5 (IL-1R5, known as IL-18 alpha chain), which is the ligandbinding chain for mature IL-18; this binding is of low affinity
Markedly elevated plasma IL-18 levels are present in patients with systemic juvenile idiopathic arthritis or systemic inflammatory adult-onset Still’s disease (AOSD), which are at high risk of developing lifethreatening macrophage activation syndrome (MAS) [22, 39, 42, 44, 45]
Different from IL-18-binding protein (IL-18BP), our antibody selectively binds the human IL-1R7 with a high affinity in the nanomolar range and prevents IL-18 signaling without affecting the anti-inflammatory signaling of IL-37 (Figure 6 and Fig. S5) [26]
Summary
18 forms a signaling complex by binding to the IL-1 receptor 5 (IL-1R5, known as IL-18 alpha chain), which is the ligandbinding chain for mature IL-18; this binding is of low affinity. Effects of the anti-IL-1R7 antibodies on IL-18-mediated proinflammatory signaling and cytokine production in human cell lines We carried out experiments using in vitro cell model systems to characterize the activity of the anti-hIL-1R7 antibodies in blocking IL-18-mediated proinflammatory signaling and cytokine production.
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