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

Affiliation
University of Cologne ,Faculty of Medicine and University Hospital Cologne ,Department of Neurology ,Cologne ,Germany
Klein, Ines;
Affiliation
University of Cologne ,Faculty of Medicine and University Hospital Cologne ,Department of Neurology ,Cologne ,Germany
Boenert, Janne;
Affiliation
University of Cologne ,Faculty of Medicine and University Hospital Cologne ,Department of Neurology ,Cologne ,Germany
Lange, Felix;
Affiliation
University of Cologne ,Faculty of Medicine and University Hospital Cologne ,Department of Neurology ,Cologne ,Germany
Christensen, Britt;
Affiliation
University of Cologne ,Faculty of Medicine and University Hospital Cologne ,Department of Neurology ,Cologne ,Germany
Wassermann, Meike K.;
Affiliation
Center of Pharmacology ,Therapeutic Drug Monitoring ,University Hospital of Cologne ,Cologne ,Germany
Wiesen, Martin H. J.;
Affiliation
University of Cologne ,Faculty of Medicine and University Hospital Cologne ,Department of Neurology ,Cologne ,Germany
Olschewski, Daniel Navin;
Affiliation
University of Cologne ,Faculty of Medicine and University Hospital Cologne ,Department of Neurology ,Cologne ,Germany
Rabenstein, Monika;
Affiliation
Center of Pharmacology ,Therapeutic Drug Monitoring ,University Hospital of Cologne ,Cologne ,Germany
Müller, Carsten;
Affiliation
University of Cologne ,Faculty of Medicine and University Hospital Cologne ,Department of Neurology ,Cologne ,Germany
Lehmann, Helmar C.;
Affiliation
University of Cologne ,Faculty of Medicine and University Hospital Cologne ,Department of Neurology ,Cologne ,Germany
Fink, Gereon Rudolf;
Affiliation
University of Cologne ,Faculty of Medicine and University Hospital Cologne ,Department of Neurology ,Cologne ,Germany
Schroeter, Michael;
Affiliation
University of Cologne ,Faculty of Medicine and University Hospital Cologne ,Department of Neurology ,Cologne ,Germany
Rueger, Maria Adele;
Affiliation
University of Cologne ,Faculty of Medicine and University Hospital Cologne ,Department of Neurology ,Cologne ,Germany
Vay, Sabine Ulrike

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.

Graphical Abstract Main Points: Paclitaxel differentially modulates inflammatory and regenerative properties of glial cells; Paclitaxel affects glia-glia and glia-neuron interactions; Paclitaxel induces pro-inflammatory effects in microglia and satellite glial cells and anti-inflammatory effects in astrocytes.

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License Holder: Copyright © 2022 Klein, Boenert, Lange, Christensen, Wassermann, Wiesen, Olschewski, Rabenstein, Müller, Lehmann, Fink, Schroeter, Rueger and Vay.

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