Wei Zhang, Zhenwei Xu
This study explores the role of the src homology-2domain-containing protein tyrosine phosphatase-2 (SHP2)-discoid domain receptor 1 (DDR1)-extracellular signal-regulated kinase (ERK) signaling axis in neuropathic pain following spinal cord injury (SCI). Rats were transfected with LV-shSHP2 before SCI modeling. Hind limb function and paw withdrawal threshold were assessed using the Basso-Beattie-Bresnahan (BBB) scale, and Von Frey filaments, respectively. The effects of SHP2 knockdown on microglial activation and DDR1/SHP2/ERK pathway were examined by Western blotting and immunofluorescence. To further validate the regulatory mechanism of SHP2 in SCI, lipopolysaccharide (LPS)-activated BV-2 microglial cells were subjected to SHP2/DDR1 knockdown, or DDR1 overexpression. Results showed that SCI induced motor deficits, mechanical allodynia, and upregulation of spinal SHP2, DDR1, and p-ERK/ERK ratio, alongside microglial activation. These changes were reversed by LV-shSHP2 treatment. In LPS treated BV-2 cells, DDR1 overexpression promoted cell activation and ERK phosphorylation, while counteracting the effects of LV-shSHP2; however, DDR1 knockdown produced the opposite effects. A direct interaction between SHP2 and DDR1 was confirmed. In conclusion, SHP2 knockdown suppresses microglial hyperactivation and alleviates SCI-induced neuropathic pain by downregulating the DDR1-ERK signaling pathway, during which SHP2-DDR1 interaction has been confirmed as a key regulatory mechanism. Targeting this specific interaction axis may offer a novel therapeutic strategy for neuropathic pain management by selectively disrupting microglial activation.