Myeloid AEG-1 regulates the initiation of chronic inflammatory pain responses in the CFA mouse model

Astrocyte elevated gene-1 (AEG-1), also known as metadherin or LYRIC, is a well-established tumor necrosis factor-alpha inducible oncogene. AEG-1 mRNA is ubiquitously expressed in all normal tissues, and at high levels in myeloid lineage cells. As a relatively novel scaffolding protein, the full spectrum of physiological functions involving AEG-1 is still not well known. AEG-1 protein regulates inflammation through its direct interaction with nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a key regulator of pro-inflammatory cytokines (PICs). Using both global (AEG-1 KO) and myeloid-specific knockout (AEG-1^ΔMAC) transgenic mouse strains, we aimed to determine whether AEG-1 influences the development of pain-like behaviors and neuroinflammation in a mouse model of complete Freund's adjuvant (CFA)-induced inflammatory pain. We hypothesized that deletion of AEG1 expression in myeloid cells, such as monocytes and macrophages, would prevent the initiation of chronic pain and associated neuroinflammation. The results showed that CFA-induced mechanical and thermal hypersensitivity were reduced in both AEG-1 KO and AEG-1^ΔMAC mice. Additionally, CFA was found to upregulate the expression of AEG-1 and several PICs in the lumbar dorsal root ganglia of wild-type mice. However, in the absence of AEG-1, PIC expression mirrored vehicle controls. Lastly, AEG-1^ΔMAC mice displayed a similar protective phenotype and PIC expression profile as AEG-1 KO mice. In summary, our results highlight for the first time the involvement of AEG-1 expression, particularly in myeloid cells, in the development of chronic inflammatory pain. Our results suggest the therapeutic potential of targeting AEG-1 for chronic inflammatory pain.