Upregulation of NLRP3 via STAT3-dependent histone acetylation contributes to painful neuropathy induced by bortezomib.

Upregulation of NLRP3 via STAT3-dependent histone acetylation contributes to painful neuropathy induced by bortezomib.
Exp Neurol. 2018 Jan 12;:
Authors: Liu CC, Huang ZX, Li X, Shen KF, Liu M, Ouyang HD, Zhang SB, Ruan YT, Zhang XL, Wu SL, Xin WJ, Ma C
Abstract
Painful neuropathy, as a severe side effect of chemotherapeutic bortezomib, is the most common reason for treatment discontinuation. However, the mechanism by which administration of bortezomib leads to painful neuropathy remains unclear. In the present study, we found that application of bortezomib significantly increased the expression of NOD-like receptor family pyrin domain containing 3 (NLRP3) and phosphorylated signal transducer and activator of transcription-3 (STAT3) in dorsal root ganglion (DRG). Intrathecal injection of NLRP3 siRNA significantly prevented the mechanical allodynia induced by bortezomib treatment, and intrathecal injection of recombinant adeno-associated virus vector encoding NLRP3 markedly decreased paw withdrawal threshold of naive rats. Furthermore, the expressions of p-STAT3 were colocalized with NLRP3-positive cells in DRG neurons, and inhibition of STAT3 by intrathecal injection of AAV-Cre-GFP into STAT3flox/flox mice or inhibitor S3I-201 suppressed the upregulation of NLRP3 and mechanical allodynia induced by bortezomib treatment. Chromatin immunoprecipitation further found that bortezomib increased the recruitment of STAT3, as well as the acet...

Source: Experimental Neurology - January 12, 2018 Category: Neurology Authors: Liu CC, Huang ZX, Li X, Shen KF, Liu M, Ouyang HD, Zhang SB, Ruan YT, Zhang XL, Wu SL, Xin WJ, Ma C Tags: Exp Neurol Source Type: research