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. 2021 Oct 16;9(2):385–450. doi: 10.1007/s40487-021-00168-y

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© The Author(s) 2021

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

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Fig. 2 — The current hypothesis for the pathogenesis of TIPN. Taxanes such as paclitaxel directly interact with TLR-4 on macrophages. This interaction upregulates the expression of TLR-4 and activates macrophages leading to the release of NF-kB, leading to further downstream pro-inflammatory cascades. Activated Langerhans cells release IL-6, IL-8, IL-10 and MCP-1. Subsequently, there is activation and migration of macrophages, cytotoxic T-cells, monocytes and neutrophils towards the DRG and peripheral nerves. DRG neurons and IB4-/GCRP+ peripheral fibres increase expression of inflammatory associated markers such as TLR4, MyD88 and ERK1/2. Similarly, inflammatory signalling is increased in Schwann cells, microglia and DRG neurons together with markers of cellular stress. Oxidative stress and the generation of ROS further impacts upon mitochondrial performance, limits intracellular energy stores of peripheral neurons and contributes to inflammation and intracellular damage. Further, taxanes such as paclitaxel interact with the MPTP, which culminates in a reduction in ATP generation and mitochondrial generation. Taxanes disrupt microtubule polymerisation and impair the function of the axonal microtubule network. The expression of CaV 3.2 and NaV 1.7 are upregulated after treatment with taxanes, resulting in changes to the excitability threshold of peripheral neurons. The sensitisation of peripheral neurons and subsequent changes in neuronal excitability result in mechanical hypersensitivity and ectopic spontaneous activity which contribute to the development of TIPN. ATP: adenosine triphosphate, CaV: low voltage-activated T-type calcium channel, CGRP: calcitonin gene-related peptide, DAMP: damage-associated molecular pattern, DRG: dorsal root ganglion, ERK1/2: extracellular signal-regulated kinase, IB4: isolectin B4-binding glycoprotein, IL-6: interleukin 6, IL-8: interleukin 8, IL-10: interleukin 10, NaV: voltage-gated sodium, NF-kB: nuclear factor kappa B, MCP-1: monocyte chemoattractant protein-1, MEK: mitogen-activated protein kinase kinase, ROS: reactive oxygen species, TIPN: taxane-induced peripheral neuropathy, TLR-4: toll-like receptor 4