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

Ines Klein; Janne Boenert; Felix Lange; Britt Christensen; Meike K Wassermann; Martin H J Wiesen; Daniel Navin Olschewski; Monika Rabenstein; Carsten Müller; Helmar C Lehmann; Gereon Rudolf Fink; Michael Schroeter; Maria Adele Rueger; Sabine Ulrike Vay

doi:10.3389/fphar.2022.1038285

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

Front Pharmacol. 2022 Nov 2:13:1038285. doi: 10.3389/fphar.2022.1038285. eCollection 2022.

Authors

Ines Klein¹, Janne Boenert¹, Felix Lange¹, Britt Christensen¹, Meike K Wassermann¹, Martin H J Wiesen², Daniel Navin Olschewski¹, Monika Rabenstein¹, Carsten Müller², Helmar C Lehmann¹, Gereon Rudolf Fink^{1

3}, Michael Schroeter^{1

3}, Maria Adele Rueger^{1

3}, Sabine Ulrike Vay¹

Affiliations

¹ University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Neurology, Cologne, Germany.
² Center of Pharmacology, Therapeutic Drug Monitoring, University Hospital of Cologne, Cologne, Germany.
³ Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Centre Juelich, Juelich, Germany.

Abstract

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.

Keywords: BDNF (brain derived neurotrophic factor); astrocytes; chemotherapy-related neurotoxicity; microglia; neural stem cells; neuroinflammation; paclitaxel; satellite glia cells.