Bando Yoshio, Suzuki Yasuhiro, Murakami Chisato, Kimura Takashi, Yahara Osamu
Department of Anatomy, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Akita, Japan.
Department of Functional Anatomy and Neuroscience, Asahikawa Medical University, 2-1-1-1 Midorigaoka Higashi, Asahikawa 078-8510, Hokkaido, Japan.
Int J Mol Sci. 2025 Apr 27;26(9):4160. doi: 10.3390/ijms26094160.
Chitinase-3-like protein 1 (CHI3L1) has been implicated in multiple sclerosis (MS) pathology, yet its precise role remains unclear. To elucidate its involvement, we performed proteomic analysis of cerebrospinal fluid (CSF) from relapsing-remitting MS (RRMS) patients using two-dimensional difference gel electrophoresis (2D-DIGE). CHI3L1 emerged as the most upregulated protein in recurrent RRMS. ELISA confirmed significantly elevated CHI3L1 levels in recurrent RRMS and secondary progressive MS (SPMS) patients, with levels decreasing in steroid responders but increasing in non-responders. Immunohistochemistry of MS brain autopsies revealed CHI3L1 expression predominantly in mature oligodendrocytes. In an experimental autoimmune encephalomyelitis (EAE) model, CHI3L1 was highly expressed in the spinal cord, particularly in oligodendrocytes and microglia/macrophages. Functional studies demonstrated that recombinant CHI3L1 (rCHI3L1) protected oligodendrocytes from LPC-induced cell death by attenuating ER stress (GRP78, ORP150). Moreover, rCHI3L1 counteracted IFN-β- and PSL-mediated inhibition of oligodendrocyte differentiation. In microglia, rCHI3L1 suppressed LPS-induced proinflammatory markers (IL-1β, iNOS). In vivo, rCHI3L1 administration significantly mitigated EAE severity by reducing gliosis, demyelination, and axonal degeneration. These findings highlight CHI3L1 as a critical modulator of neuroinflammation and oligodendrocyte survival, positioning it as a promising therapeutic target for MS.
几丁质酶-3样蛋白1（CHI3L1）与多发性硬化症（MS）的病理过程有关，但其确切作用仍不清楚。为了阐明其作用，我们使用二维差异凝胶电泳（2D-DIGE）对复发缓解型MS（RRMS）患者的脑脊液（CSF）进行了蛋白质组学分析。CHI3L1是复发型RRMS中上调最为明显的蛋白质。酶联免疫吸附测定（ELISA）证实复发型RRMS和继发进展型MS（SPMS）患者的CHI3L1水平显著升高，在类固醇反应者中水平降低，而在无反应者中升高。MS脑尸检的免疫组织化学显示CHI3L1主要在成熟少突胶质细胞中表达。在实验性自身免疫性脑脊髓炎（EAE）模型中，CHI3L1在脊髓中高表达，特别是在少突胶质细胞和小胶质细胞/巨噬细胞中。功能研究表明，重组CHI3L1（rCHI3L1）通过减轻内质网应激（GRP78、ORP150）保护少突胶质细胞免受溶血磷脂酰胆碱（LPC）诱导的细胞死亡。此外，rCHI3L1抵消了IFN-β和泼尼松龙（PSL）介导的对少突胶质细胞分化的抑制作用。在小胶质细胞中，rCHI3L1抑制LPS诱导的促炎标志物（IL-1β、诱导型一氧化氮合酶（iNOS））。在体内，给予rCHI3L1可通过减少胶质增生、脱髓鞘和轴突变性显著减轻EAE的严重程度。这些发现突出了CHI3L1作为神经炎症和少突胶质细胞存活的关键调节因子，使其成为MS有前景的治疗靶点。
