Nalbandian Angèle, Khan Arif A, Srivastava Ruchi, Llewellyn Katrina J, Tan Baichang, Shukr Nora, Fazli Yasmin, Kimonis Virginia E, BenMohamed Lbachir
Laboratory of Cellular and Molecular Immunology, Gavin Herbert Institute, School of Medicine, University of California Irvine, Irvine, CA, 92697, USA.
Division of Genetics and Genomics Medicine, Department of Pediatrics, University of California Irvine, Irvine, CA, 92697, USA.
Inflammation. 2017 Feb;40(1):21-41. doi: 10.1007/s10753-016-0449-5.
Aberrant activation of the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome, triggers a pathogenic inflammatory response in many inherited neurodegenerative disorders. Inflammation has recently been associated with valosin-containing protein (VCP)-associated diseases, caused by missense mutations in the VCP gene. This prompted us to investigate whether NLRP3 inflammasome plays a role in VCP-associated diseases, which classically affects the muscles, bones, and brain. In this report, we demonstrate (i) an elevated activation of the NLRP3 inflammasome in VCP myoblasts, derived from induced pluripotent stem cells (iPSCs) of VCP patients, which was significantly decreased following in vitro treatment with the MCC950, a potent and specific inhibitor of NLRP3 inflammasome; (ii) a significant increase in the expression of NLRP3, caspase 1, IL-1β, and IL-18 in the quadriceps muscles of VCP heterozygote mice, an experimental mouse model that has many clinical features of human VCP-associated myopathy; (iii) a significant increase of number of IL-1βF4/80Ly6C inflammatory macrophages that infiltrate the muscles of VCP mice; (iv) NLRP3 inflammasome activation and accumulation IL-1βF4/80Ly6C macrophages positively correlated with high expression of TDP-43 and p62/SQSTM1 markers of VCP pathology in damaged muscle; and (v) treatment of VCP mice with MCC950 inhibitor suppressed activation of NLRP3 inflammasome, reduced the F4/80Ly6CIL-1β macrophage infiltrates in the muscle, and significantly ameliorated muscle strength. Together, these results suggest that (i) NLRP3 inflammasome and local IL-1βF4/80Ly6C inflammatory macrophages contribute to pathogenesis of VCP-associated myopathy and (ii) identified MCC950 specific inhibitor of the NLRP3 inflammasome with promising therapeutic potential for the treatment of VCP-associated myopathy.
NOD样受体（NLR）家族含pyrin结构域蛋白3（NLRP3）炎性小体的异常激活，在许多遗传性神经退行性疾病中引发致病性炎症反应。炎症最近与含缬酪肽蛋白（VCP）相关疾病相关，这些疾病由VCP基因的错义突变引起。这促使我们研究NLRP3炎性小体是否在VCP相关疾病中起作用，VCP相关疾病通常影响肌肉、骨骼和大脑。在本报告中，我们证明：（i）源自VCP患者诱导多能干细胞（iPSC）的VCP成肌细胞中NLRP3炎性小体的激活升高，在用NLRP3炎性小体的强效特异性抑制剂MCC950进行体外处理后显著降低；（ii）在VCP杂合子小鼠的股四头肌中，NLRP3、半胱天冬酶1、白细胞介素-1β和白细胞介素-18的表达显著增加，VCP杂合子小鼠是一种具有人类VCP相关肌病许多临床特征的实验小鼠模型；（iii）浸润VCP小鼠肌肉的白细胞介素-1β⁺F4/80⁺Ly6C⁺炎性巨噬细胞数量显著增加；（iv）NLRP3炎性小体激活和IL-1β⁺F4/80⁺Ly6C⁺巨噬细胞积累与受损肌肉中VCP病理的TDP-43和p62/SQSTM1标志物的高表达呈正相关；（v）用MCC950抑制剂治疗VCP小鼠可抑制NLRP3炎性小体的激活，减少肌肉中F4/80⁺Ly6C⁺IL-1β⁺巨噬细胞浸润，并显著改善肌肉力量。总之，这些结果表明：（i）NLRP3炎性小体和局部IL-1β⁺F4/80⁺Ly6C⁺炎性巨噬细胞促成VCP相关肌病的发病机制；（ii）鉴定出NLRP3炎性小体的MCC950特异性抑制剂，对治疗VCP相关肌病具有有前景的治疗潜力。
