Shirasawa Eiki, Uchida Kentaro, Onuma Kenji, Inoue Gen, Eshima Koji, Satoh Masashi, Miyagi Masayuki, Toyomura Yoji, Norisugi Akira, Takaso Masashi
Department of Orthopaedic Surgery, Kitasato University School of Medicine, Sagamihara 252-0374, Kanagawa, Japan.
Medical Sciences Research Institute, Shonan University, Chigasaki 253-0083, Kanagawa, Japan.
NeuroSci. 2025 Jun 29;6(3):59. doi: 10.3390/neurosci6030059.
Peripheral nerve injury initiates a complex cascade of events coordinating immune responses, extracellular matrix (ECM) remodeling, and neuronal repair. While β2-microglobulin (B2M) is well known for its role in MHC class I-mediated antigen presentation and CD8 T-cell differentiation, its potential contributions to non-immune processes remain underexplored. In this study, we investigated the role of B2M in peripheral nerve regeneration using a chronic constriction injury (CCI) model in wild-type and B2M-deficient (B2M-KO) mice. Flow cytometry, RNA sequencing (RNA-seq), and quantitative PCR (qPCR) were performed to assess T-cell subset dynamics and gene expression following injury. Flow cytometric analysis showed that CD3CD4 and CD3CD8 T-cell populations increased by day 7 post-injury. While CD3CD4 T-cell expansion occurred in both groups, a significant increase in CD3CD8 T cells was observed only in wild-type mice. RNA-seq analysis at 3 days post-injury-prior to substantial T-cell accumulation-revealed marked downregulation of ECM-related genes in B2M-KO mice, including collagens, matrix-associated proteins, and other key ECM components. KEGG analysis identified suppression of ECM-receptor interaction, PI3K-Akt, and TGF-β signaling pathways. qPCR confirmed reduced expression of Thbs1 in B2M-KO mice. These findings suggest that B2M plays a critical, CD8 T-cell-independent role in regulating ECM dynamics and regenerative signaling during early nerve repair, expanding the conceptual framework of B2M's function beyond classical immune roles.
周围神经损伤引发了一系列复杂的事件，协调免疫反应、细胞外基质（ECM）重塑和神经元修复。虽然β2微球蛋白（B2M）因其在MHC I类介导的抗原呈递和CD8 T细胞分化中的作用而广为人知，但其对非免疫过程的潜在贡献仍未得到充分探索。在本研究中，我们使用慢性压迫损伤（CCI）模型，在野生型和B2M缺陷（B2M-KO）小鼠中研究了B2M在周围神经再生中的作用。进行了流式细胞术、RNA测序（RNA-seq）和定量PCR（qPCR），以评估损伤后T细胞亚群的动态变化和基因表达。流式细胞术分析显示，损伤后第7天CD3⁺CD4⁺和CD3⁺CD8⁺ T细胞群体增加。虽然两组均出现CD3⁺CD4⁺ T细胞扩增，但仅在野生型小鼠中观察到CD3⁺CD8⁺ T细胞显著增加。损伤后3天的RNA-seq分析（在大量T细胞积累之前）显示，B2M-KO小鼠中ECM相关基因显著下调，包括胶原蛋白、基质相关蛋白和其他关键ECM成分。KEGG分析确定了ECM受体相互作用、PI3K-Akt和TGF-β信号通路的抑制。qPCR证实B2M-KO小鼠中Thbs1的表达降低。这些发现表明，B2M在早期神经修复过程中调节ECM动态和再生信号方面发挥着关键的、不依赖CD8 T细胞的作用，扩展了B2M功能的概念框架，超越了经典的免疫作用。
