美国布莱根妇女医院Francisco J. Quintana小组的最新研究揭示了在多发性硬化症小鼠模型中，星形胶质细胞中的CLEC16A促进有丝分裂并限制病理。相关论文发表在2025年3月3日出版的《自然—神经科学》杂志上。

在一项基于CRISPR的全基因组正向遗传筛选中，研究了星形胶质细胞促炎反应的调节因子，小组发现含有C型凝集素结构域的16A基因（CLEC16A）与MS易感性相关，是核因子-κB （NF-κB）信号传导的抑制因子。在小鼠原代和人胚胎干细胞来源的星形胶质细胞中进行的基因和小分子微扰研究，结合多组学分析证实，CLEC16A促进线粒体自噬，限制线粒体功能障碍和线粒体产物的积累，这些产物激活NF-κB、NLRP3炎性小体和气胶蛋白D。星形胶质细胞特异性CLEC16A失活增加体内NF-κB、NLRP3和气胶蛋白D的激活，加重实验性自身免疫性脑脊膜炎，这是多发性硬化症的主题模型。

此外，该研究团队在MS患者的星形胶质细胞中检测到有丝分裂能力和气真皮蛋白D激活的破坏。这些发现确定了CLEC16A作为星形细胞病理反应的抑制因子和MS的候选治疗靶点。

研究人员表示，星形胶质细胞通过细胞内在活动及其招募和激活其他细胞类型的能力促进多发性硬化症（MS）的神经炎症和神经退行性变。

附：英文原文

Title: CLEC16A in astrocytes promotes mitophagy and limits pathology in a multiple sclerosis mouse model

Author: Kadowaki, Atsushi, Wheeler, Michael A., Li, Zhaorong, Andersen, Brian M., Lee, Hong-Gyun, Illouz, Tomer, Lee, Joon-Hyuk, Ndayisaba, Alain, Zandee, Stephanie E. J., Basu, Himanish, Chao, Chun-Cheih, Mahler, Joao V., Klement, Wendy, Neel, Dylan, Bergstresser, Matthew, Rothhammer, Veit, Lipof, Gabriel, Srun, Lena, Soleimanpour, Scott A., Chiu, Isaac, Prat, Alexandre, Khurana, Vikram, Quintana, Francisco J.

Issue&Volume: 2025-03-03

Abstract: Astrocytes promote neuroinflammation and neurodegeneration in multiple sclerosis (MS) through cell-intrinsic activities and their ability to recruit and activate other cell types. In a genome-wide CRISPR-based forward genetic screen investigating regulators of astrocyte proinflammatory responses, we identified the C-type lectin domain-containing 16A gene (CLEC16A), linked to MS susceptibility, as a suppressor of nuclear factor-κB (NF-κB) signaling. Gene and small-molecule perturbation studies in mouse primary and human embryonic stem cell-derived astrocytes in combination with multiomic analyses established that CLEC16A promotes mitophagy, limiting mitochondrial dysfunction and the accumulation of mitochondrial products that activate NF-κB, the NLRP3 inflammasome and gasdermin D. Astrocyte-specific Clec16a inactivation increased NF-κB, NLRP3 and gasdermin D activation in vivo, worsening experimental autoimmune encephalomyelitis, a mouse model of MS. Moreover, we detected disrupted mitophagic capacity and gasdermin D activation in astrocytes in samples from individuals with MS. These findings identify CLEC16A as a suppressor of astrocyte pathological responses and a candidate therapeutic target in MS.

DOI: 10.1038/s41593-025-01875-9

Source: https://www.nature.com/articles/s41593-025-01875-9