%0 Journal Article
%T TRAF6 promotes spinal microglial M1 polarization to aggravate neuropathic pain by activating the c-JUN/NF-kB signaling pathway.
%A Zhao Y
%A Li T
%A Zhang L
%A Yang J
%A Zhao F
%A Wang Y
%A Ouyang Y
%A Liu J
%J Cell Biol Toxicol
%V 40
%N 1
%D 2024 Jul 12
%M 38995476
%F 6.819
%R 10.1007/s10565-024-09900-6
%X <B>BACKGROUND: </B>The neuropathic pain with complex networks of neuroinflammatory activation severely limits clinical therapeutic research. TNF receptor-associated factor 6 (TRAF6) is associated with multiple inflammatory diseases. However, there remains confusion about the effects and mechanisms of TRAF6 in neuropathic pain.<BR><B>METHODS: </B>A chronic constriction injury (CCI) model was developed to simulate neuralgia in vivo. We overexpressed or knocked down TRAF6 in CCI mice, respectively. Activation of microglia by TRAF6, the inflammatory response, and disease progression were inspected using WB, qRT-PCR, immunofluorescence, flow cytometry, and ELISA assays. Moreover, the mechanism of M1/M2 polarization activation of microglia by TRAF6 was elaborated in BV-2 cells.<BR><B>RESULTS: </B>TRAF6 was enhanced in the spinal neurons and microglia of the CCI mice model compared with the sham operation group.. Down-regulation of TRAF6 rescued the expression of Iba-1. In response to mechanical and thermal stimulation, PWT and PWL were improved after the knockdown of TRAF6. Decreased levels of pro-inflammatory factors were observed in TRAF6 knockdown groups. Meanwhile, increased microglial M1 markers induced by CCI were limited in mice with TRAF6 knockdown. In addition, TRAF6 overexpression has the precise opposite effect on CCI mice or microglia polarization. We also identifed that TRAF6 activated the c-JUN/NF-kB pathway signaling; the inhibitor of c-JUN/NF-kB could effectively alleviate the neuropathic pain induced by upregulated TRAF6 in the CCI mice model.<BR><B>CONCLUSIONS: </B>In summary, this study indicated that TRAF6 was concerned with neuropathic pain, and targeting the TRAF6/c-JUN/NF-kB pathway may be a prospective target for treating neuropathic pain.