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
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
Nat Neurosci. 2025 Mar;28(3):470-486. doi: 10.1038/s41593-025-01875-9. Epub 2025 Mar 3.
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.
星形胶质细胞通过细胞内在活性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）中的神经炎症和神经退行性变。在一项基于全基因组CRISPR的正向遗传筛选中，我们研究了星形胶质细胞促炎反应的调节因子，确定了与MS易感性相关的含C型凝集素结构域16A基因（CLEC16A），它是核因子-κB（NF-κB）信号通路的抑制因子。在小鼠原代和人胚胎干细胞衍生的星形胶质细胞中进行的基因和小分子干扰研究，结合多组学分析表明，CLEC16A促进线粒体自噬，限制线粒体功能障碍以及激活NF-κB、NLRP3炎性小体和gasdermin D的线粒体产物的积累。星形胶质细胞特异性Clec16a失活在体内增加了NF-κB、NLRP3和gasdermin D的激活，加重了实验性自身免疫性脑脊髓炎，这是一种MS小鼠模型。此外，我们在MS患者的样本中检测到星形胶质细胞的线粒体自噬能力受损和gasdermin D激活。这些发现确定CLEC16A是星形胶质细胞病理反应的抑制因子，也是MS的候选治疗靶点。
