The upregulation of NLRP3 inflammasome in dorsal root ganglion by ten-eleven translocation methylcytosine dioxygenase 2 (TET2) contributed to diabetic neuropathic pain in mice

• DOI: 10.1186/s12974-022-02669-7
• Publication Date: 2022-12-16T05:06:00Z
• Authors: Wen Chen; Xiaotong Wang; Qingyu Sun; Yurui Zhang; Jing Liu; Tingting Hu; Weihua Wu; Chao Wei; Meng Liu; Yumeng Ding; Dianxin Liu; Yingzi Chong; Peipei Wang; Hongwei Zhu; Weihua Cui; Jiannan Zhang; Qian Li; Fei Yang
• Keywords: Transcriptional Activation; TET2; 0303 health sciences; Inflammasomes; Research; NLRP3 inflammasome; Streptozocin; Diabetes Mellitus, Experimental; Up-Regulation; Dioxygenases; Epigenesis, Genetic; DNA-Binding Proteins; Mice; 03 medical and health sciences; Diabetic Neuropathies; Ganglia, Spinal; NLR Family, Pyrin Domain-Containing 3 Protein; Diabetic neuropathic pain; Animals; Neuralgia; Dorsal root ganglion; Neurology. Diseases of the nervous system; RC346-429

Abstract Background The nucleotide oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) in dorsal root ganglion (DRG) contributes to pain hypersensitivity in multiple neuropathic pain models, but the function of the NLRP3 in diabetic neuropathic pain (DNP) and the regulation mechanism are still largely unknown. Epigenetic regulation plays a vital role in the controlling of gene expression. Ten-eleven translocation methylcytosine dioxygenase 2 (TET2) is a DNA demethylase that contributes to transcriptional activation. TET2 is also involved in high glucose (HG)-induced pathology.

Methods DNP was induced in mice via the intraperitoneal injection of streptozotocin (STZ) for five consecutive days and the mechanical threshold was evaluated in STZ-diabetic mice by using von Frey hairs. The expression level of the NLRP3 pathway and TET2 in DRG were determined through molecular biology experiments. The regulation of the NLRP3 pathway by TET2 was examined in in vitro and in vivo conditions.

Results In the present research, we first established the DNP model and found that NLRP3 pathway was activated in DRG. The treatment of NLRP3 inhibitor MCC950 alleviated the mechanical allodynia of DNP mice. Then we revealed that in STZ-diabetic mice DRG, the genomic DNA was demethylated, and the expression of DNA demethylase TET2 was increased evidently. Using RNA-sequencing analysis, we found that the expression of Txnip, a gene that encodes a thioredoxin-interacting protein (TXNIP) which mediates NLRP3 activation, was elevated in the DRG after STZ treatment. In addition, knocking down of TET2 expression in DRG using TET2-siRNA suppressed the mRNA expression of Txnip and subsequently inhibited the expression/activation of NLRP3 inflammasome in vitro and in vivo as well as relieved the pain sensitivity of DNP animals.

Conclusion The results suggested that the upregulation of the TXNIP/NLRP3 pathway by TET2 in DRG was involved in the pain hypersensitivity of the DNP model.