| Autor: |
Jiang, Shihe, Li, Xindi, Li, Yan, Chang, Zhilin, Yuan, Meng, Zhang, Ying, Zhu, Huimin, Xiu, Yuwen, Cong, Hengri, Yin, Linlin, Yu, Zhen-Wei, Fan, Junwan, He, Wenyan, Shi, Kaibin, Tian, De-Cai, Zhang, Jing, Verkhratsky, Alexei, Jin, Wei-Na, Shi, Fu-Dong |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 2/28/2024, Vol. 16 Issue 736, p1-15, 15p |
| Abstrakt: |
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy of the central nervous system, mediated by antibodies against aquaporin-4 water channel protein (AQP4-Abs), resulting in damage of astrocytes with subsequent demyelination and axonal damage. Extracellular communication through astrocyte-derived extracellular vesicles (ADEVs) has received growing interest in association with astrocytopathies. However, to what extent ADEVs contribute to NMOSD pathogenesis remains unclear. Here, through proteomic screening of patient-derived ADEVs, we observed an increase in apolipoprotein E (APOE)–rich ADEVs in patients with AQP4-Abs–positive NMOSD. Intracerebral injection of the APOE-mimetic peptide APOE130–149 attenuated microglial reactivity, neuroinflammation, and brain lesions in a mouse model of NMOSD. The protective effect of APOE in NMOSD pathogenesis was further established by the exacerbated lesion volume in APOE-deficient mice, which could be rescued by exogenous APOE administration. Genetic knockdown of the APOE receptor lipoprotein receptor–related protein 1 (LRP1) could block the restorative effects of APOE130–149 administration. The transfusion ADEVs derived from patients with NMOSD and healthy controls also alleviated astrocyte loss, reactive microgliosis, and demyelination in NMOSD mice. The slightly larger beneficial effect of patient-derived ADEVs as compared to ADEVs from healthy controls was further augmented in APOE−/− mice. These results indicate that APOE from astrocyte-derived extracellular vesicles could mediate disease-modifying astrocyte-microglia cross-talk in NMOSD. Editor's summary: Neuromyelitis optica spectrum disorder (NMOSD) is a demyelinating central nervous system disorder initiated by an astrocyte-targeted autoimmune response. Here, Jiang et al. investigated how signaling by astrocytic extracellular vesicles (ADEVs) affects NMOSD pathogenesis. The researchers found increased expression of apolipoprotein E in patient-derived ADEVs and showed that administration of ADEVs or an APOE-mimicking peptide decreased neuroinflammation and brain lesions in a mouse model of NMOSD. The protective effects of APOE were blocked by genetic deletion of low-density lipoprotein receptor–related protein 1 (LRP1). These results suggest that signaling by ADEVs might keep neuroinflammation and progression of NMOSD in check. —Daniela Neuhofer [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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