PDF(Pubmed)
Abstract：
UNASSIGNED: Interleukin-18 (IL-18), a pro-inflammatory cytokine belonging to the IL-1 Family, is a key mediator ofautoinflammatory diseases associated with the development of macrophage activation syndrome (MAS).High levels of IL-18 correlate with MAS and COVID-19 severity and mortality, particularly in COVID-19patients with MAS. As an inflammation inducer, IL-18 binds its receptor IL-1 Receptor 5 (IL-1R5), leadingto the recruitment of the co-receptor, IL-1 Receptor 7 (IL-1R7). This heterotrimeric complex subsequentlyinitiates downstream signaling, resulting in local and systemic inflammation.
UNASSIGNED: We reported earlier the development of a novel humanized monoclonal anti-human IL-1R7 antibody whichspecifically blocks the activity of human IL-18 and its inflammatory signaling in human cell and wholeblood cultures. In the current study, we further explored the strategy of blocking IL-1R7 inhyperinflammation in vivo using animal models.
UNASSIGNED: We first identified an anti-mouse IL-1R7 antibody that significantly suppressed mouse IL-18 andlipopolysaccharide (LPS)-induced IFNg production in mouse splenocyte and peritoneal cell cultures. Whenapplied in vivo, the antibody reduced Propionibacterium acnes and LPS-induced liver injury and protectedmice from tissue and systemic hyperinflammation. Importantly, anti-IL-1R7 significantly inhibited plasma,liver cell and spleen cell IFNg production. Also, anti-IL-1R7 downregulated plasma TNFa, IL-6, IL-1b,MIP-2 production and the production of the liver enzyme ALT. In parallel, anti-IL-1R7 suppressed LPSinducedinflammatory cell infiltration in lungs and inhibited the subsequent IFNg production andinflammation in mice when assessed using an acute lung injury model.
UNASSIGNED: Altogether, our data suggest that blocking IL-1R7 represents a potential therapeutic strategy to specificallymodulate IL-18-mediated hyperinflammation, warranting further investigation of its clinical application intreating IL-18-mediated diseases, including MAS and COVID-19.
UNASSIGNED: We reported earlier the development of a novel humanized monoclonal anti-human IL-1R7 antibody whichspecifically blocks the activity of human IL-18 and its inflammatory signaling in human cell and wholeblood cultures. In the current study, we further explored the strategy of blocking IL-1R7 inhyperinflammation in vivo using animal models.
UNASSIGNED: We first identified an anti-mouse IL-1R7 antibody that significantly suppressed mouse IL-18 andlipopolysaccharide (LPS)-induced IFNg production in mouse splenocyte and peritoneal cell cultures. Whenapplied in vivo, the antibody reduced Propionibacterium acnes and LPS-induced liver injury and protectedmice from tissue and systemic hyperinflammation. Importantly, anti-IL-1R7 significantly inhibited plasma,liver cell and spleen cell IFNg production. Also, anti-IL-1R7 downregulated plasma TNFa, IL-6, IL-1b,MIP-2 production and the production of the liver enzyme ALT. In parallel, anti-IL-1R7 suppressed LPSinducedinflammatory cell infiltration in lungs and inhibited the subsequent IFNg production andinflammation in mice when assessed using an acute lung injury model.
UNASSIGNED: Altogether, our data suggest that blocking IL-1R7 represents a potential therapeutic strategy to specificallymodulate IL-18-mediated hyperinflammation, warranting further investigation of its clinical application intreating IL-18-mediated diseases, including MAS and COVID-19.
摘要：
■白细胞介素-18（IL-18），属于IL-1家族的促炎细胞因子，是与巨噬细胞活化综合征（MAS）发展相关的自身炎症性疾病的关键介质。高水平的IL-18与MAS和COVID-19严重程度和死亡率相关，特别是COVID-19MAS患者。作为炎症诱导剂，IL-18结合其受体IL-1受体5（IL-1R5），导致共受体的招募，IL-1受体7(IL-1R7)。这种异源三聚体复合物随后启动下游信号，导致局部和全身炎症。
我们较早报道了新型人源化单克隆抗人IL-1R7抗体的开发，该抗体特异性阻断人IL-18的活性及其在人细胞和全血培养物中的炎症信号传导。在目前的研究中,我们使用动物模型进一步探索了体内阻断IL-1R7炎症过度的策略。
我们首先鉴定了一种抗小鼠IL-1R7抗体，该抗体显着抑制小鼠脾细胞和腹膜细胞培养物中小鼠IL-18和脂多糖（LPS）诱导的IFNg产生。当应用于体内时，该抗体减少了痤疮丙酸杆菌和LPS诱导的肝损伤，并保护小鼠免受组织和全身性炎症。重要的是,抗IL-1R7显著抑制血浆，肝细胞和脾细胞产生IFNg。此外，抗IL-1R7下调血浆TNFα，IL-6,IL-1b,MIP-2的产生和肝酶ALT的产生。并行,当使用急性肺损伤模型评估时，抗IL-1R7抑制了LPS诱导的肺部炎症细胞浸润，并抑制了随后的IFNg产生和小鼠炎症。
■总之，我们的数据表明，阻断IL-1R7是特异性调节IL-18介导的炎症过度的潜在治疗策略，保证进一步研究其在治疗IL-18介导的疾病的临床应用，包括MAS和COVID-19。
我们较早报道了新型人源化单克隆抗人IL-1R7抗体的开发，该抗体特异性阻断人IL-18的活性及其在人细胞和全血培养物中的炎症信号传导。在目前的研究中,我们使用动物模型进一步探索了体内阻断IL-1R7炎症过度的策略。
我们首先鉴定了一种抗小鼠IL-1R7抗体，该抗体显着抑制小鼠脾细胞和腹膜细胞培养物中小鼠IL-18和脂多糖（LPS）诱导的IFNg产生。当应用于体内时，该抗体减少了痤疮丙酸杆菌和LPS诱导的肝损伤，并保护小鼠免受组织和全身性炎症。重要的是,抗IL-1R7显著抑制血浆，肝细胞和脾细胞产生IFNg。此外，抗IL-1R7下调血浆TNFα，IL-6,IL-1b,MIP-2的产生和肝酶ALT的产生。并行,当使用急性肺损伤模型评估时，抗IL-1R7抑制了LPS诱导的肺部炎症细胞浸润，并抑制了随后的IFNg产生和小鼠炎症。
■总之，我们的数据表明，阻断IL-1R7是特异性调节IL-18介导的炎症过度的潜在治疗策略，保证进一步研究其在治疗IL-18介导的疾病的临床应用，包括MAS和COVID-19。
