Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Rd., Chongqing, 400016, China.
College of Stomatology, Chongqing Key Laboratory for Oral Diseases and Biomedical Science, Chongqing Medical University, Chongqing, China.
Biochem Biophys Res Commun. 2020 Jun 4;526(3):772-779. doi: 10.1016/j.bbrc.2020.03.161. Epub 2020 Apr 4.
Recent evidence suggests that Propionibacterium acnes (P. acnes) is a novel pathogenic factor promoting intervertebral disc degeneration (IVDD), however, whose mechanism remains unclear. A key component of inflammatory responses to P. acnes appears to be interleukin (IL)-1β, which has been proved to be high expression in degenerative nucleus pulposus cells (NPCs). This study aimed to explore the inflammatory mechanism driving the host response to P. acnes infection in IVDD. Our data demonstrated that the number of nod-like receptor protein 3 (NLRP3)-positive cells was significantly increased in the P. acnes-infected nucleus pulposus (NP) tissue. Meanwhile, the up-regulated expressions of NLRP3, caspase-1, caspase-5, IL-1β, IL-18, Gasdermin D (GSDMD) were observed in NPCs after co-culturing with P. acnes, which suggested NPCs pyroptosis activation induced by P. acnes. To further investigate the underlying mechanisms, NLRP3 inflammasome inhibitor MCC950 and thioredoxin binding protein (TXNIP)-siRNA were used. With the addition of MCC950 to NPCs co-cultured with P. acnes in vitro, the secretions of mature IL-1β and IL-18 were reduced. Moreover, these MCC950-mediated effects were repeated by siRNA-transfected TXNIP knockdown. These results implied P. acnes activated inflammatory response by the TXNIP-NLRP3 pathway. To further reveal the anti-degeneration role of MCC950 in vivo, MCC950 was injected into the rabbit IVDD models infected by P. acnes. The MRI and histological detection provided more solid evidence that MCC950 treatment effectively retarded the degenerative process of the intervertebral discs in vivo. In summary, these results suggest that P. acnes-induced NPCs pyroptosis activation via the NLRP3-dependent pathway is likely responsible for the inflammatory pathology of IVDD. MCC950 can alleviate inflammatory injury and NPCs pyroptosis under P. acnes infection and may delay the progression of disc degeneration, which provides a new direction for the treatment of IVDD.
最近的证据表明，痤疮丙酸杆菌（P. acnes）是一种促进椎间盘退变（IVDD）的新型致病因素，但其机制尚不清楚。炎症反应中 P. acnes 的一个关键组成部分似乎是白细胞介素（IL）-1β，已被证明在退变核髓细胞（NPC）中高表达。本研究旨在探讨导致宿主对 P. acnes 感染的炎症反应的炎症机制。我们的数据表明，在 P. acnes 感染的核髓（NP）组织中，NOD 样受体蛋白 3（NLRP3）阳性细胞的数量明显增加。同时，在与 P. acnes 共培养后，NPC 中观察到 NLRP3、半胱天冬酶-1、半胱天冬酶-5、IL-1β、IL-18、Gasdermin D（GSDMD）的表达上调，提示 P. acnes 诱导 NPC 细胞焦亡。为了进一步探讨其潜在机制，我们使用了 NLRP3 炎症小体抑制剂 MCC950 和硫氧还蛋白结合蛋白（TXNIP）-siRNA。在体外与 P. acnes 共培养的 NPC 中加入 MCC950 后，成熟的 IL-1β 和 IL-18 的分泌减少。此外，这些 MCC950 介导的作用可通过转染 TXNIP-siRNA 进行重复。这些结果表明，P. acnes 通过 TXNIP-NLRP3 通路激活炎症反应。为了进一步揭示 MCC950 在体内的抗退变作用，将 MCC950 注射到感染 P. acnes 的兔 IVDD 模型中。MRI 和组织学检测提供了更确凿的证据，表明 MCC950 治疗可有效延缓体内椎间盘的退变过程。综上所述，这些结果表明，P. acnes 诱导 NPC 细胞焦亡激活可能是通过 NLRP3 依赖性途径导致 IVDD 的炎症病理学的原因。MCC950 可减轻 NPCs 在 P. acnes 感染下的炎症损伤和细胞焦亡，可能延缓椎间盘退变的进展，为 IVDD 的治疗提供了新的方向。
