The selective inhibitors for heat shock protein 90 beta reduce the lipopolysaccharide (LPS)‐induced inflammatory response via inhibiting the activation of NF‐κB and ERK MAPK in BV2 microglial cells

Abstract

Neuroinflammation contributes to several health conditions related to the central nervous system, such as Alzheimer’s Disease and pain. Understanding the regulation of neuroinflammation is essential for discovering approaches to treat inflammation‐related diseases. Previous studies demonstrated that the inhibition of Heat shock protein 90 (Hsp90) using 17‐N‐allylamino‐17‐demethoxygeldanamycin (17‐AAG) could reduce neuroinflammation. However, the contribution of Hsp90 isoforms, including Hsp90α, Hsp90β, glucose‐regulated protein 94 (Grp94), and tumor necrosis factor type 1 (TRAP1), to inflammatory signaling remain poorly understood. This study aimed to determine the impact of selective inhibitors for Hsp90β on lipopolysaccharide (LPS)‐induced inflammatory responses in microglial cells. A murine microglial cell line, BV‐2 cells, were pretreated with selective inhibitors for Hsp90β for 1 hour, followed by the stimulation of LPS. The production of Nitric Oxide (NO) was measured using Griess Reagents, and qPCR was performed to detect the expression of tumor necrosis factor‐alpha (TNF‐α) and Interleukin‐1 beta (IL‐1β). In addition, the activation of the nuclear factor‐κB (NF‐κB) and Nrf2 were investigated. The impact of selected inhibitors on the activation of extracellular‐signal‐regulated kinases (ERK), p38 mitogen‐activated protein kinases (p38 MAPK), and c‐Jun‐N‐terminal kinases (JNK) was measured using Western Blots. We found that treatment with Hsp90β inhibitorsstrongly inhibited the production of NO, TNF‐α, and IL‐1β, and the activation of NF‐κB, but showed a modest effect on Nrf2 activation. Additionally, the Hsp90β inhibitors also showed to inhibit the activation of ERK, but no effect on p38 and JNK activation. These findings demonstrate that Hsp90β plays a vital role in the LPS‐induced neuroinflammation in microglial cells.