TREM1 inhibition via LP17 alleviates secondary spinal cord injury by activating AMPKα-PINK1-parkin-dependent microglial mitophagy

Spinal cord injury (SCI) is characterized by primary mechanical trauma and subsequent secondary pathogenic cascades, with chronic neuroinflammation impeding neurological functional recovery. Microglial activation, mitochondrial dysfunction, and mitophagy are key pathological players, while the role of triggering receptor expressed on myeloid cells 1 (TREM1) in SCI remains incompletely elucidated. This study explored TREM1 targeting and the regulation of microglial mitophagy in SCI using 8-week-old female C57BL/6 J mice and BV2 microglial cells. Mice were administered the TREM1 inhibitor LP17 or physiological saline. Assessments included behavioral evaluations, Nissl staining, immunofluorescence staining, Western blot analysis, and transmission electron microscopy. We found that TREM1 expression peaked at 3 days post-SCI and was specifically localized to microglia. LP17 inhibited TREM1 expression, improved 4-week post-injury Basso Mouse Scale scores and footprint parameters, reduced Nissl body loss, and downregulated proinflammatory mediators in the spinal cord and lipopolysaccharide (LPS)-stimulated BV2 cells. LP17 enhanced LPS-induced mitophagy in BV2 cells and activated the AMPKα-PINK1-Parkin signaling pathway. Small interfering RNA-mediated AMPKα knockdown (si-AMPKα) blocked LP17-induced mitophagy and its anti-inflammatory effects. In conclusion, LP17 inhibits TREM1 to alleviate secondary SCI via the AMPKα-PINK1-Parkin-dependent microglial mitophagy pathway, making TREM1 a potential therapeutic target for SCI.