Introduction Altered complement component 3 (C3) activation in patients with alpha-1 antitrypsin (AAT) deficiency (AATD) has been reported. To understand the potential impact on course of inflammation, the aim of this study was to investigate whether C3d, a cleavage-product of C3, triggers interleukin (IL)-1β secretion via activation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. The objective was to explore the effect of AAT augmentation therapy in patients with AATD on the C3d/complement receptor 3 (CR3) signalling axis of monocytes and on circulating pro-inflammatory markers. Methods Inflammatory mediators were detected in blood from patients with AATD (n=28) and patients with AATD receiving augmentation therapy (n=19). Inflammasome activation and IL-1β secretion were measured in monocytes of patients with AATD, and following C3d stimulation in the presence or absence of CR3 or NLRP3 inhibitors. Results C3d acting via CR3 induces NLRP3 and pro-IL-1β production, and through induction of endoplasmic reticulum (ER) stress and calcium flux, triggers caspase-1 activation and IL-1β secretion. Treatment of individuals with AATD with AAT therapy results in decreased plasma levels of C3d (3.0±1.2 µg/mL vs 1.3±0.5 µg/mL respectively, p<0.0001) and IL-1β (115.4±30 pg/mL vs 73.3±20 pg/mL, respectively, p<0.0001), with a 2.0-fold decrease in monocyte NLRP3 protein expression (p=0.0303), despite continued ER stress activation. Discussion These results provide strong insight into the mechanism of complement-driven inflammation associated with AATD. Although the described variance in C3d and NLRP3 activation decreased post AAT augmentation therapy, results demonstrate persistent C3d and monocyte ER stress, with implications for new therapeutics and clinical practice. All data that support the findings in this study are available from the corresponding author upon request.

中文翻译：

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缺陷个体中 α-1 抗胰蛋白酶治疗调节单核细胞 NLRP3 炎性体和白细胞介素 1β 激活

简介 据报道，α-1 抗胰蛋白酶 (AAT) 缺乏症 (AATD) 患者的补体成分 3 (C3) 激活发生了改变。为了了解对炎症过程的潜在影响，本研究的目的是研究 C3d（C3 的裂解产物）是否通过激活包含 NOD-、LRR- 和 Pyrin 结构域的蛋白质来触发白细胞介素 (IL)-1β 分泌3 (NLRP3) 炎性小体。目的是探讨 AAT 增强治疗对 AATD 患者的单核细胞 C3d/补体受体 3 (CR3) 信号轴和循环促炎标志物的影响。方法检测 AATD 患者 (n=28) 和接受增强治疗的 AATD 患者 (n=19) 血液中的炎症介质。在存在或不存在 CR3 或 NLRP3 抑制剂的情况下，在 C3d 刺激后，测量 AATD 患者单核细胞中的炎症小体激活和 IL-1β 分泌。结果 C3d 通过 CR3 作用，诱导 NLRP3 和 pro-IL-1β 产生，并通过诱导内质网 (ER) 应激和钙流，触发 caspase-1 激活和 IL-1β 分泌。使用 AAT 疗法治疗 AATD 患者会导致血浆 C3d 水平降低（分别为 3.0±1.2 µg/mL 与 1.3±0.5 µg/mL，p<0.0001）和 IL-1β（115.4±30 pg/mL 与 73.3±20 pg/mL） pg/mL，p<0.0001），尽管持续的 ER 应激激活，单核细胞 NLRP3 蛋白表达下降了 2.0 倍（p=0.0303）。讨论 这些结果提供了对与 AATD 相关的补体驱动炎症机制的深入了解。尽管所描述的 C3d 和 NLRP3 激活差异在 AAT 增强治疗后减少，但结果表明持续的 C3d 和单核细胞 ER 应激，这对新的治疗方法和临床实践具有影响。支持本研究结果的所有数据均可根据要求从通讯作者处获得。