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.
CONCLUSIONS: 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.
方法:在AATD患者(n=28)和接受强化治疗的AATD患者(n=19)的血液中检测到炎症介质。在AATD患者的单核细胞中测量炎症小体激活和IL-1β分泌,以及在存在或不存在CR3或NLRP3抑制剂的情况下的C3d刺激之后。
结果:通过CR3作用的C3d诱导NLRP3和pro-IL-1β的产生,并通过诱导内质网(ER)应激和钙通量,触发caspase-1激活和IL-1β分泌。用AAT治疗AATD个体导致血浆C3d水平降低(分别为3.0±1.2µg/mL和1.3±0.5µg/mL,p<0.0001)和IL-1β(115.4±30pg/mLvs73.3±20pg/mL,分别,p<0.0001),单核细胞NLRP3蛋白表达减少2.0倍(p=0.0303),尽管持续的ER压力激活。
结论:这些结果对补体驱动的与AATD相关的炎症机制提供了强有力的见解。尽管在AAT增强治疗后C3d和NLRP3激活的所述变化减少,结果表明持续的C3d和单核细胞内质网应激,对新疗法和临床实践的影响。