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.
【저자키워드】 COVID-19, therapeutic, macrophage activation syndrome (MAS), IBD, Inflammatory bowel disease, blockade, IFNγ, IL-1 receptor 7 (IL-1R7), interleukin-18 (IL-18), AOSD, adult-onset Still's disease, DSS, dextran sodium sulfate, IL-18, interleukin-18, MAS, macrophage activation syndrome, PBMC, peripheral blood mononuclear cell, sHLH, secondary hemophagocytic lymphohistiocytosis, TIR, Toll-IL-1 receptor, TNSB, trinitrobenzoic sulfonic acid, 【초록키워드】 Inflammation, Cytokine storm, Diseases, antibody, IL-6, Symptoms, Peripheral blood, Whole blood, severity of COVID-19, Alpha, macrophage activation syndrome, receptor, recruitment, IL-1, therapeutic strategy, COVID-19 patients, monoclonal, human cell lines, LPS, Interleukin-18, Signaling, PBMCs, severe disease, COVID-19 patient, mononuclear cell, Proinflammatory cytokine, Activation, complex, IFNγ, high mortality, TNFα, cultures, systemic hyperinflammation, IL-18, downstream, NFκB, humanized, inflammatory signaling, bind, resulting, significantly, inhibited, elevated, reduced, characterized, modulate, suppressed, exhibiting, initiate, Candida albican, systemic and local, 【제목키워드】 antibody, inflammatory signaling, reduce,