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

Bryan D Mckiver; Sara M Herz; Shivani Patel; Tayla Bryan; Jared Mann; Justin L Poklis; John W Bigbee; Jolene J Windle; Aliasger K Salem; Devanand Sarkar; M Imad Damaj

doi:10.1016/j.bbi.2025.03.020

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

Journal article

Peer reviewed

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

Bryan D Mckiver, Sara M Herz, Shivani Patel, Tayla Bryan, Jared Mann, Justin L Poklis, John W Bigbee, Jolene J Windle, Aliasger K Salem, Devanand Sarkar, …

Brain, behavior, and immunity, Vol.127, pp.329-340

07/2025

DOI: 10.1016/j.bbi.2025.03.020

PMID: 40101807

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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.

Inflammation

Pain

AEG-1/MTDH

CIPN

Neuropathy

Details

Title: Subtitle: Astrocyte elevated gene-1 (AEG-1) in myeloid cells is a key driver for the development of chemotherapy-induced peripheral neuropathy
Creators: Bryan D Mckiver - Virginia Commonwealth University
Sara M Herz - Virginia Commonwealth University
Shivani Patel - Virginia Commonwealth University
Tayla Bryan - Virginia Commonwealth University
Jared Mann - Virginia Commonwealth University
Justin L Poklis - Virginia Commonwealth University
John W Bigbee - Virginia Commonwealth University
Jolene J Windle - Virginia Commonwealth University
Aliasger K Salem - University of Iowa
Devanand Sarkar - Virginia Commonwealth University
M Imad Damaj - Virginia Commonwealth University
Resource Type: Journal article
Publication Details: Brain, behavior, and immunity, Vol.127, pp.329-340
DOI: 10.1016/j.bbi.2025.03.020
PMID: 40101807
NLM abbreviation: Brain Behav Immun
ISSN: 0889-1591
eISSN: 1090-2139
Publisher: ACADEMIC PRESS INC ELSEVIER SCIENCE
Grant note: National Institutes of Health: 5R25GM090084-12, 5T32CA093423-13, 1F31CA275450-01A1, P30 DA033934 VCU Massey Comprehensive Cancer Center Transgenic/Knockout Mouse, Microscopy, and Flow Cytometry Shared ResourcesNIH-NCI Cancer Center Support Grant: P30 CA016059
This work was supported by funds from the National Institutes of Health: 1R61NS127287 to M.I.D and D.S; 5R25GM090084-12, 5T32CA093423-13, and 1F31CA275450-01A1 to B.M; P30 DA033934 to JLP. Services in support of this research project were provided by the VCU Massey Comprehensive Cancer Center Transgenic/Knockout Mouse, Microscopy, and Flow Cytometry Shared Resources, supported, in part, with funding from NIH-NCI Cancer Center Support Grant P30 CA016059.
Language: English
Electronic publication date: 03/16/2025
Date published: 07/2025
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Research Administration; Pharmaceutical Sciences and Experimental Therapeutics; Craniofacial Anomalies Research Center; Dental Research; Chemical and Biochemical Engineering
Record Identifier: 9984801617302771

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