Department of Laboratory Medicine, Nanjing First Hospital, Nanjng Medical University, Nanjing 210006, China.
Department of Laboratory Medicine, Jiangning Hospital Affiliated to Nanjng Medical University, Nanjing 211100, China.
Int Immunopharmacol. 2024 May 30;133:112096. doi: 10.1016/j.intimp.2024.112096. Epub 2024 Apr 23.
Severe myocarditis is often accompanied by cardiac fibrosis, but the underlying mechanism has not been fully elucidated. NOD-like receptor protein 3 (NLRP3) inflammation is involved in the development of myocarditis and is closely related to the form of cell death. Inhibiting pyroptosis mediated by NLRP3 inflammasome can reduce cardiac fibrosis, although its exact mechanism remains unknown. In this study, we induced Viral myocarditis (VMC) via infection of CVB3 to explore the relationship between pyroptosis and fibrosis. Our results showed that intraperitoneal injection of an NLRP3 inhibitor MCC950 or use of NLRP3 mice inhibited cardiac pyroptosis mediated by NLRP3 inflammasome in VMC. CXCL4 is a chemokine that has been reported to have pro-inflammatory and pro-fibrotic functions. In VMC, we further found that pyroptosis of Mouse myocardial fibroblasts (MCF) promoted the secretion of CXCL4 by activating Wnt/β-Catenin signaling. Subsequently, the transcriptome sequencing data showed that CXCL4 could promote cardiac fibrosis by activating PI3K/AKT pathway. In summary, infection of CVB3 induced host oxidative stress to further activate the NLRP3 inflammasome and ultimately lead to heart pyroptosis, in which MCF secreted CXCL4 by activating Wnt/β-Catenin signaling and CXCL4 participated in cardiac fibrosis by activating PI3K/AKT pathway. Therefore, our findings revealed the role of CXCL4 in VMC and unveiled its underlying mechanism. CXCL4 appears to be a potential target for the treatment of VMC.
严重心肌炎常伴有心肌纤维化，但其中的机制尚未完全阐明。NOD 样受体蛋白 3（NLRP3）炎症参与了心肌炎的发展，并且与细胞死亡的形式密切相关。抑制 NLRP3 炎性小体介导的细胞焦亡可以减少心肌纤维化，尽管其确切机制尚不清楚。在这项研究中，我们通过感染 CVB3 诱导病毒性心肌炎（VMC），以探索细胞焦亡与纤维化之间的关系。我们的结果表明，腹腔注射 NLRP3 抑制剂 MCC950 或使用 NLRP3 敲除小鼠可抑制 VMC 中 NLRP3 炎性小体介导的心脏细胞焦亡。趋化因子 CXCL4 已被报道具有促炎和促纤维化作用。在 VMC 中，我们进一步发现，心肌成纤维细胞（MCF）的细胞焦亡通过激活 Wnt/β-Catenin 信号通路促进 CXCL4 的分泌。随后，转录组测序数据显示，CXCL4 通过激活 PI3K/AKT 通路促进心脏纤维化。总之，CVB3 感染诱导宿主氧化应激，进一步激活 NLRP3 炎性小体，最终导致心脏细胞焦亡，其中 MCF 通过激活 Wnt/β-Catenin 信号通路分泌 CXCL4，而 CXCL4 通过激活 PI3K/AKT 通路参与心脏纤维化。因此，我们的研究结果揭示了 CXCL4 在 VMC 中的作用及其潜在机制。CXCL4 似乎是治疗 VMC 的一个有潜力的靶点。
