Contributions of neuroimmune interactions to chemotherapy-induced peripheral neuropathy development and its prevention/therapy

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating sequela that is difficult for both clinicians and cancer patients to manage. Precise mechanisms of CIPN remain elusive and current clinically prescribed therapies for CIPN have limited efficacy. Recent studies have begun investigating the interactions between the peripheral and central nervous systems and the immune system. Understanding these neuroimmune interactions may shift the paradigm of elucidating CIPN mechanisms. Although the contribution of immune cells to CIPN pathogenesis represents a promising area of research, its fully defined mechanisms have not yet been established. Therefore, in this review, we will discuss (i) current shortcoming of CIPN treatments, (ii) the roles of neuroimmune interactions in CIPN development and (iii) potential neuroimmune interaction-targeting treatment strategies for CIPN. Interestingly, monocytes/macrophages in dorsal root ganglia; microglia and astrocytes in spinal cord; mast cells in skin; and Schwann cell near peripheral nerves have been identified as inducers of CIPN behaviors, whereas T cells have been found to contribute to CIPN resolution. Additionally, nerve-resident immune cells have been targeted as prevention and/or therapy for CIPN using traditional herbal medicines, small molecule inhibitors, and intravenous immunoglobulins in a preclinical setting. Overall, unveiling neuroimmune interactions associated with CIPN may ultimately reduce cancer mortality and improve cancer patients' quality of life.

Keywords: Adverse effects; Chemotherapy-induced peripheral neuropathy; Neuroimmune interaction; Quality of life.

Figure 1.. The mechanisms whereby immune cells contribute to the development of chemotherapy-induced peripheral neuropathy.

Dorsal root ganglia (DRG) sensory nerve fibers extend to the periphery of the body and are known to interact with immune cells. Both innate and adaptive immune responses following chemotherapeutic insults have been proposed to be involved in the development of chemotherapy-induced peripheral neuropathy (CIPN). Additionally, the chemotherapy-mediated activation or deactivation of the spinal immune cells has been thought to be a part of the mechanisms of CIPN development. The infiltration of monocytes/macrophages in nervous tissues plays crucial roles of CIPN development. Indeed, (i) the upregulation of monocyte chemoattractant protein-1 (MCP-1) expression in DRG following oxaliplatin treatment; (ii) the elevated levels of galectin-3 in Schwann cells within the sciatic nerve following paclitaxel treatment; and (iii) the enhanced vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) expression in endothelial cells following vincristine treatment are responsible for the monocyte/macrophage infiltration, resulting in CIPN development. Specifically, after binding to endothelial cells, these infiltrating monocytes/macrophages are activated through the C-X3-C motif chemokine ligand 1 (CX3CL1) from endothelial cell/C-X3-C motif chemokine receptor 1 (CXCR1) on monocyte/macrophage axis and then produce reactive oxygen species (ROS). The resulting ROS then activate transient receptor potential ankyrin 1 (TRPA1) receptor on sciatic nerves, leading to increased vincristine-mediated peripheral neuropathy. In the skin environment, oxaliplatin and paclitaxel enhance tryptase and histamine release from mast cells, respectively. The mast cell-derived tryptase and histamine are also known to induce CIPN. In the spinal cord, (i) cisplatin increases triggering receptor expressed on myeloid cells 2 (TREM2), known to be involved in inflammatory cytokine production, in microglia; and (ii) oxaliplatin reduces the levels of insulin-like growth factor-1 (IGF1), known to maintain nerve survival, in astrocytes. Conversely, T cells have protective roles from CIPN. Paclitaxel-exposed T cells stimulate interleukin-10 (IL-10) production from macrophages through IL-13. Macrophage-derived IL-10 blocks the paclitaxel-induced peripheral neuropathy by binding to IL-10 receptor (IL-10R) on DRG. Graphics adapted from Smart Servier Medical Art (https://smart.servier.com/).