DataSheet2_Glia from the central and peripheral nervous system are differentially affected by paclitaxel chemotherapy via modulating their neuroinflammatory and neuroregenerative properties.pdf

Glia are critical players in defining synaptic contacts and maintaining neuronal homeostasis. Both astrocytes as glia of the central nervous system (CNS), as well as satellite glial cells (SGC) as glia of the peripheral nervous system (PNS), intimately interact with microglia, especially under pathological conditions when glia regulate degenerative as well as regenerative processes. The chemotherapeutic agent paclitaxel evokes peripheral neuropathy and cognitive deficits; however, the mechanisms underlying these diverse clinical side effects are unclear. We aimed to elucidate the direct effects of paclitaxel on the function of astrocytes, microglia, and SGCs, and their glia-glia and neuronal-glia interactions. After intravenous application, paclitaxel was present in the dorsal root ganglia of the PNS and the CNS of rodents. In vitro, SGC enhanced the expression of pro-inflammatory factors and reduced the expression of neurotrophic factor NT-3 upon exposure to paclitaxel, resulting in predominantly neurotoxic effects. Likewise, paclitaxel induced a switch towards a pro-inflammatory phenotype in microglia, exerting neurotoxicity. In contrast, astrocytes expressed neuroprotective markers and increasingly expressed S100A10 after paclitaxel exposure. Astrocytes, and to a lesser extent SGCs, had regulatory effects on microglia independent of paclitaxel exposure. Data suggest that paclitaxel differentially modulates glia cells regarding their (neuro-) inflammatory and (neuro-) regenerative properties and also affects their interaction. By elucidating those processes, our data contribute to the understanding of the mechanistic pathways of paclitaxel-induced side effects in CNS and PNS.

神经胶质细胞（Glia）是构建突触连接、维持神经元稳态的核心参与者。作为中枢神经系统（CNS）胶质细胞的星形胶质细胞（astrocytes），以及外周神经系统（PNS）胶质细胞的卫星胶质细胞（SGC），均与小胶质细胞（microglia）存在密切相互作用，这一现象在胶质细胞调控退行性与再生过程的病理状态下尤为突出。
化疗药物紫杉醇（paclitaxel）可诱发周围神经病与认知功能缺损，但其引发这类多样化临床副作用的潜在机制仍未阐明。本研究旨在解析紫杉醇对星形胶质细胞、小胶质细胞及卫星胶质细胞功能的直接影响，以及它们之间的胶质-胶质与神经元-胶质相互作用模式。
静脉给药后，紫杉醇可在啮齿类动物的外周神经系统背根神经节与中枢神经系统中检测到。体外实验结果显示，卫星胶质细胞在暴露于紫杉醇后，促炎因子表达水平上调，而神经营养因子NT-3（NT-3）的表达则被抑制，最终主要介导神经毒性效应。与之类似，紫杉醇可诱导小胶质细胞向促炎表型转化，进而发挥神经毒性作用。
与此形成对比的是，星形胶质细胞会表达神经保护标志物，且在紫杉醇暴露后S100A10的表达水平显著升高。星形胶质细胞（以及作用程度较弱的卫星胶质细胞）可在不依赖紫杉醇暴露的前提下对小胶质细胞产生调控作用。
本研究数据表明，紫杉醇可基于胶质细胞的（神经）炎症与（神经）再生特性对其产生差异化调控，同时也会影响胶质细胞间的相互作用。通过阐明上述过程，本研究成果有助于深化对紫杉醇诱导的中枢神经系统与外周神经系统副作用的机制通路的认知。