Peripheral myeloid cells control resolution of painful Chemotherapy-Induced Peripheral Neuropathy (CIPN) (S23.001)

Abstract

<h3>Objective:</h3> The objective of this study is to identify endogenous mediators controlling CIPN pain resolution. <h3>Background:</h3> Chemotherapies contribute to decreased cancer mortality but are associated with severe side effects including Chemotherapy-Induced Peripheral Neuropathy (CIPN). CIPN presents as a distal symmetric polyneuropathy causing numbness, tingling, and in a subset of patients, pain. Painful CIPN is a main cause for chemotherapy dose reduction, treatment cessation and reduced quality of life. A subset of painful CIPN patients will have pain resolution while others maintain pain persistency, however the mechanisms that mediate pain resolution are unknown and constitute a large gap of knowledge. <h3>Design/Methods:</h3> We developed painful CIPN models in mice using the chemotherapeutic paclitaxel, where mice treated with specific injection protocols develop resolving or persistent mechanical hypersensitivity measured via von Frey. Using these models, we performed bulk RNA sequencing on hind paw, whole dorsal root ganglion (DRG), DRG sensory neurons and spinal cord at initiation, pre-resolution, post-resolution, and persistency time points. DEGs were selected (P-adj &lt;0.05, FC &gt; 2, RPKM &gt; 1) and PANTHER analysis was performed to identify biological processes. To investigate the contribution of particular cell types in these tissues, we used the inducible diphtheria toxin receptor ablation model. <h3>Results:</h3> PANTHER analysis identified upregulation of immune system related genes in the hind paw during resolution of Model-1 not seen in Model-2. As myeloid cells are known to contribute to immune system related genes in the periphery, we ablated myeloid cells. We identified that CD11b+ peripheral, but not IBA1+ central, myeloid cells are critical for painful CIPN resolution. Further RNA sequencing analysis identified pro-inflammatory pathways correlated with painful CIPN resolution. <h3>Conclusions:</h3> These studies provide mechanistic insights for CIPN pain resolution and identify a unique therapeutic strategy for permanent treatment of painful CIPN. Future studies will delineate the myeloid cell sub-type and factors required for CIPN pain resolution. <b>Disclosure:</b> Mr. Naratadam has nothing to disclose. Prof. Akopian has nothing to disclose.