57: TREM1 enhance spinal M1 microglia polarization and mitochondrial dysfunction in neuropathic pain

Topic: Basic Science
Subtopic: Pain category (ICD-11), Chronic neuropathic pain, , , , , , , , , , Neuroimmunology, Pharmacological interventions

Background and Aims: Objective: The activation of the triggering receptor expressed on myeloid cells 1 (TREM1) potentiates innate immunity by triggering the induction of pro-inflammatory mediators from neutrophils and monocytes. We previously showed that TREM1 fuels chronic neuropathic pain (NP), yet the downstream mechanisms remain unclear. Here, we aimed to investigate whether TREM1 triggers NP by skewing microglial toward the M1 phenotype and suppressing neuronal AMPK/PGC-1α signaling, thereby impairing mitochondrial function.

Methods: Methods: To establish a mouse model of neuropathic pain, we employed the spared nerve injury (SNI) procedure. The development of mechanical allodynia was evaluated based on the mechanical paw withdrawal threshold (MPWT). To elucidate the roles of TREM1 and the AMPK/PGC-1α axis, we employed a combination of techniques including Western blotting, immunofluorescence staining, ELISA, biochemical analyses, and transmission electron microscopy. TREM1 was blocked pharmacologically (LP17 peptide) or genetically (TREM1-/- mice), and compound C was utilized as an AMPK inhibitor to ensure pathway specificity.

Results: Results: After SNI, TREM1 levels were significantly elevated within the spinal dorsal horn (SDH), primarily localizing to microglia. Either LP17 treatment or TREM1 deletion prevented mechanical allodynia, reduced M1 markers (iNOS, CD32), and lowered IL-1β and TNF-α release. TREM1 inhibition restored AMPK phosphorylation and PGC-1α expression, normalized mitochondrial ultrastructure, increased ATP, SOD and GSH levels, and decreased ROS. Co-administration of compound C abolished the analgesic and mitochondrial-protective effects of LP17, confirming the AMPK/PGC-1α pathway as the key downstream route of TREM1.

Conclusions: Conclusion: Our findings demonstrate that TREM1 activation promoted microglia M1 polarization, induced mitochondrial dysfunction via suppressing the neuronal AMPK/PGC-1α signaling, ultimately lead to NP. These results support the therapeutic potential of TREM1 antagonism in mitigating NP.

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Presenting Author: xiaoyu zhang
Submitting Author: xiaoyu zhang

Senior Author: xuebi tian

IASP 2026 Global Year theme of Neuropathic Pain: Yes

• Xuebi Tian: professor - Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
• wen zhang: NA - Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China