Spinal TREM2/PI3K/Akt signal axis elicits microglial activation and aggravates bone cancer pain

J Anesth Transl Med. 2025 Jun 13;4(2):91-101. doi: 10.1016/j.jatmed.2025.04.002. eCollection 2025 Jun.

ABSTRACT

BACKGROUND: The TREM2 signaling pathway is activated in multiple pain conditions; nevertheless, its role in the regulation of bone cancer pain remains largely unexplored. The persistent pathological progression of bone cancer pain induces microglial overstimulation, leading to the exacerbation of spinal central inflammation. These results confound the neurobehavioral symptoms and obscure the underlying mechanisms. Thus, the precise mechanism by which TREM2 induces bone cancer pain (BCP) has yet to be clarified.

METHODS: Lewis lung carcinoma cells (LLC) were administered into the femoral bone marrow cavity of adult male C57BL/6J mice. Nociceptive responses were assessed utilizing von Frey and Hargreaves methods. Biochemical analysis was utilized to assess mRNA expression levels of relevant proteins and inflammatory markers in the spinal cords of the subjects, while immunofluorescence analysis was used to assess alterations in the quantity of activated microglial cells.

RESULTS: We found that the expression levels of TREM2/DAP12 genes were increased in the spinal cords of BCP mice and may influence microglial activity via activation of the PI3K/Akt signaling pathway. The intrathecal delivery of TREM2-shRNA, combined with the selective PI3K inhibitor LY2494002, significantly inhibited the overactivation of microglia in pathological states, reduced the secretion of inflammatory mediators, and consequently mitigated central neuroinflammation while reversing pain sensitization in BCP mice. Conversely, intrathecal overexpression of the TREM2 gene can also induce abnormal pain responses.

CONCLUSION: TREM2 may be the key gene involved in the hyperalgesia induced by excessive activation of spinal microglia under pathological conditions of bone cancer, which depends on the phosphorylation of the PI3K/Akt signaling axis.

PMID:41930274 | PMC:PMC13001742 | DOI:10.1016/j.jatmed.2025.04.002