Lößlein Lena, Linnerbauer Mathias, Zuber Finnja, Tsaktanis Thanos, Vandrey Oliver, Peter Anne, Panier Franziska, Zissler Julia, Riekher Vivienne, Bäuerle Tobias, Hanspach Jannis, Laun Frederik B, Nagel Lisa, Mészáros Lisa, Zunke Friederike, Winkler Jürgen, Naumann Ulrike J, Schwingen Nora, Neumaier Emely, Liesz Arthur, Quintana Francisco, Rothhammer Veit
Department of Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen Nuremberg, Erlangen, Germany.
Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates.
Nat Commun. 2025 Jun 19;16(1):5344. doi: 10.1038/s41467-025-60363-7.
After acute lesions in the central nervous system (CNS), the interaction of microglia, astrocytes, and infiltrating immune cells decides over their resolution or chronification. However, this CNS-intrinsic cross-talk is poorly characterized. Analyzing cerebrospinal fluid (CSF) samples of Multiple Sclerosis (MS) patients as well as CNS samples of female mice with experimental autoimmune encephalomyelitis (EAE), the animal model of MS, we identify microglia-derived TGFα as key factor driving recovery. Through mechanistic in vitro studies, in vivo treatment paradigms, scRNA sequencing, CRISPR-Cas9 genetic perturbation models and MRI in the EAE model, we show that together with other glial and non-glial cells, microglia secrete TGFα in a highly regulated temporospatial manner in EAE. Here, TGFα contributes to recovery by decreasing infiltrating T cells, pro-inflammatory myeloid cells, oligodendrocyte loss, demyelination, axonal damage and neuron loss even at late disease stages. In a therapeutic approach in EAE, blood-brain barrier penetrating intranasal application of TGFα attenuates pro-inflammatory signaling in astrocytes and CNS infiltrating immune cells while promoting neuronal survival and lesion resolution. Together, microglia-derived TGFα is an important mediator of glial-immune crosstalk, highlighting its therapeutic potential in resolving acute CNS inflammation.
在中枢神经系统（CNS）发生急性损伤后，小胶质细胞、星形胶质细胞和浸润性免疫细胞之间的相互作用决定了损伤是得到缓解还是转为慢性。然而，这种中枢神经系统内在的相互作用目前还鲜为人知。通过分析多发性硬化症（MS）患者的脑脊液（CSF）样本以及MS动物模型——实验性自身免疫性脑脊髓炎（EAE）雌性小鼠的中枢神经系统样本，我们确定小胶质细胞衍生的转化生长因子α（TGFα）是驱动恢复的关键因素。通过体外机制研究、体内治疗模式、单细胞RNA测序、CRISPR-Cas9基因扰动模型以及EAE模型中的磁共振成像，我们发现，在EAE中，小胶质细胞与其他神经胶质细胞和非神经胶质细胞一起，以高度受调控的时空方式分泌TGFα。在此过程中，即使在疾病晚期，TGFα也通过减少浸润性T细胞、促炎性髓样细胞、少突胶质细胞损失、脱髓鞘、轴突损伤和神经元损失，从而促进恢复。在EAE的一种治疗方法中，经鼻给予可穿透血脑屏障的TGFα，可减弱星形胶质细胞和中枢神经系统浸润性免疫细胞中的促炎信号，同时促进神经元存活和损伤修复。总之，小胶质细胞衍生的TGFα是神经胶质-免疫相互作用的重要介质，凸显了其在解决急性中枢神经系统炎症方面的治疗潜力。
