GDPD3 Deficiency Alleviates Neuropathic Pain and Reprograms Macrophagic Polarization Through PGE2 and PPARγ Pathway

• Published in: Neurochemical research 2024-08, Vol.49 (8), p.1980-1992
• Main Authors: Li, Wenqian, Fan, Youjia, Lan, Haizhen, Li, Xiaoxiao, Wu, Qichao, Dong, Rong
• Format: Article
• Language: English
• Subjects: Analgesics; Animals; Anti-inflammatory agents; Biochemistry; Biomedical and Life Sciences; Biomedicine; Celecoxib; Cell Biology; Cell Polarity - physiology; Dinoprostone - metabolism; Dorsal root ganglia; Fatty Acid-Binding Proteins - deficiency; Fatty Acid-Binding Proteins - metabolism; Ganglia; Ganglia, Spinal - metabolism; Gene sequencing; Inflammation; Lysophospholipase; Macrophages; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; mRNA; Neuralgia; Neuralgia - drug therapy; Neuralgia - metabolism; Neurochemistry; Neurology; Neurosciences; Nonsteroidal anti-inflammatory drugs; Original Paper; Pain; Peroxisome proliferator-activated receptors; Phenotypes; Polarization; PPAR gamma - metabolism; Prostaglandin E2; Signal Transduction - physiology; Switching
• ISSN: 0364-3190; 1573-6903; 1573-6903
• DOI: 10.1007/s11064-024-04148-2

The complex mechanism of neuropathic pain involves various aspects of both central and peripheral pain conduction pathways. An effective cure for neuropathic pain therefore remains elusive. We found that deficiency of the gene Gdpd3 , encoding a lysophospholipase D enzyme, alleviates the inflammatory responses in dorsal root ganglia (DRG) of mice under neuropathic pain and reduces PE (20:4) and PGE2 in DRG. Gdpd3 deficiency had a stronger analgesic effect on neuropathic pain than Celecoxib, a nonsteroidal anti-inflammatory drug. Gdpd3 deficiency also interferes with the polarization of macrophages, switching from M1 towards M2 phenotype. The PPARγ/ FABP4 pathway was screened by RNA sequencing as functional related with Gdpd3 deficient BMDMs stimulated with LPS. Both protein and mRNA levels of PPARγ in GDPD3 deficient BMDMs were higher than those of the litter control mice. However, GW9962 (inhibitor of PPARγ) could reverse the reprogramming polarization of macrophages caused by GDPD3 deficiency. Therefore, our study suggests that GDPD3 deficiency exerts a relieving effect on neuropathic pain and alleviates neuroinflammation in DRG by switching the phenotype of macrophages from M1 to M2, which was mediated through PGE2 and PPARγ/ FABP4 pathway.