Activating Fc-gamma Receptor III Mediate Sciatic Nerve Injury-induced Neuropathic Pain

Background & Aims

Neuropathic pain is difficult to treat in clinical practice, and the underlying mechanisms are insufficiently elucidated. Previous studies have demonstrated that neuronal Fc receptors may be involved in pain. However, the mechanisms of Fc?RIII in neuropathic pain remain to be explored.

Methods

RNA sequencing was used to investigate transcriptome profile changes in the spinal dorsal horn (SDH) in a mouse model of sciatic nerve injury (CCI). Wild-type (WT), Fc?R knockout (KO) and Fcgr1g KO mice were used to establish the CCI model. Behavioral, morphological, and molecular studies were conducted to evaluate the differences between WT and KO mice after CCI.

Results

We found that Fc-gamma receptors (Fc?Rs), including Fc?RI, Fc?RII, and Fc?RIII, and Fc-epsilon receptor I gamma (Fc?RI?) mRNA were upregulated in the SDH of a mouse model of CCI. Fc?RI? associates with activating Fc-gamma receptor on the cell surface to form a functional signaling complex and regulate immune responses. Meanwhile, sciatic nerve injury persistently and significantly increases the protein levels of Fc?RI, Fc?RII, Fc?RIII and Fc?RI? in the SDH after neuropathic pain. Our work also revealed that Fc?RIII and Fc?RI? were expressed in microglia of the SDH after CCI. Furthermore, knockout of the Fc?RIII-encoding gene Fcgr3 or Fc?RI?-encoding gene Fcer1g significantly alleviated neuropathic pain in mice after CCI. Overexpression of Fc?RIII or Fc?RI? in the SDH by the adeno-associated virus (AAV) vector evokes chronic pain in wild-type mice.

Conclusions

Our previous studies have first demonstrated that Fc-gamma receptors III expressed in the spinal dorsal horn can be directly activated after nerve injury via Fc?RI?-dependent signaling.
These results indicate that the microglial complex of the SDH plays an important role in the development of neuropathic pain in chronic constriction injury mice.

References

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Presenting Author