Astrocyte elevated gene-1 (AEG-1) in myeloid cells is a key driver for the development of chemotherapy-induced peripheral neuropathy.

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of chemotherapy treatment, often resulting in the discontinuation of treatment. Paclitaxel activates peripheral macrophages, generating a neuroinflammatory response that contributes to CIPN development and maintenance. Astrocyte Elevated Gene-1 (AEG-1), also known as Metadherin or LYRIC, is a multifunctional protein that modulates macrophage activity and regulates inflammation through direct interaction with NF-κB, a transcriptional regulator of proinflammatory cytokine/chemokine (PIC) expression. We aimed to determine whether AEG-1 contributes to the development and maintenance of CIPN pathologies by using both global (AEG-1 KO) and myelocyte-specific knockout (AEG-1ΔMAC) transgenic mouse strains in an animal model of CIPN that replicates specific human clinical phenotypes. We hypothesized that inhibition of AEG1 expression in myeloid cells, such as monocytes and macrophages, would prevent the development and maintenance of CIPN. Our results showed that global AEG-1 deletion prevented the development of CIPN pathologies induced by PAC, as well as oxaliplatin (OHP). PAC treatment was found to increase AEG-1 and PIC expression in the DRGs of WT mice and in peritoneal macrophages isolated from C57BL/6J mice. However, in the absence of AEG-1 expression, PAC-induced neuroinflammation was completely halted in the DRGs of AEG-1 KO mice. This preventative phenotype and PIC expression profile was mirrored in AEG-1ΔMAC mice, which also displayed reduced NF-κB protein levels and F4/80+ macrophages trafficked to the lumbar DRGs following PAC treatment. In summary, our results are the first to demonstrate the biological role AEG-1, particularly in myeloid cells, in development of CIPN.