Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medical Sciences, Fukuoka, and Department of Rheumatology, NHO Fukuoka National Hospital, Fukuoka, Japan.
Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Clin Exp Rheumatol. 2022 Mar;40(3):522-531. doi: 10.55563/clinexprheumatol/eakvlv. Epub 2021 Mar 22.
Emerging evidence has shown the importance of inflammasome activation in the progression of autoimmune diseases. In this study, we aimed to identify the main cell types activating inflammasome in autoimmune diseases and to clarify the intracellular pathway of inflammasome activation in systemic lupus erythematosus (SLE).
Active caspase-1 in each subset of human peripheral blood cells from healthy controls (n=18), SLE (n=51), and other rheumatic diseases (n=36) were fluorescently probed with FLICA™-caspase-1 followed by flow cytometric analysis. The correlation of caspase-1 activation in monocytes and clinical parameters in SLE patients were evaluated. In-vitro experiments were performed to identify the pathway involved in caspase-1 activation induced by SLE serum in monocytes.
Active caspase-1 in monocytes was upregulated in SLE patients. Cluster of differentiation 14 (CD14)-positive and CD16-positive monocytes showed considerable activation of caspase-1 compared with the other subsets of monocytes. Serum titres of anti-double stranded DNA antibodies were positively correlated with active caspase-1 in monocytes, and serum complement component 3 and platelet count were negatively correlated with active caspase-1 in monocytes. The SLE serum-induced activation of caspase-1 and IL-1β secretion were down-regulated by inhibition of NLR family pyrin domain containing 3 (NLRP3), cyclic GMP-AMP synthase (cGAS), or stimulator of interferon genes (STING).
These findings suggest that targeting inflammasome by regulating cGAS/STING and NLRP3 are potential therapeutic strategies for SLE.
新出现的证据表明炎症小体激活在自身免疫性疾病的进展中具有重要作用。本研究旨在确定在自身免疫性疾病中激活炎症小体的主要细胞类型，并阐明系统性红斑狼疮（SLE）中炎症小体激活的细胞内途径。
用 FLICA™-caspase-1 荧光探针探测健康对照者（n=18）、SLE 患者（n=51）和其他风湿性疾病患者（n=36）外周血单个核细胞中各亚群的活性半胱天冬酶-1，并用流式细胞术分析。评估 SLE 患者单核细胞中 caspase-1 激活与临床参数的相关性。进行体外实验以确定 SLE 血清在单核细胞中诱导 caspase-1 激活所涉及的途径。
SLE 患者单核细胞中活性 caspase-1 上调。与其他单核细胞亚群相比，CD14 阳性和 CD16 阳性单核细胞中 caspase-1 有可观的激活。抗双链 DNA 抗体的血清滴度与单核细胞中活性 caspase-1 呈正相关，而血清补体成分 3 和血小板计数与单核细胞中活性 caspase-1 呈负相关。NLR 家族含 pyrin 结构域蛋白 3（NLRP3）、环鸟苷酸-腺苷酸合酶（cGAS）或干扰素基因刺激物（STING）的抑制可下调 SLE 血清诱导的 caspase-1 激活和 IL-1β 分泌。
这些发现表明通过调节 cGAS/STING 和 NLRP3 靶向炎症小体可能是治疗 SLE 的潜在策略。
