FPS-ZM1 inhibits LPS-induced microglial inflammation by suppressing JAK/STAT signaling pathway

Int Immunopharmacol. 2021 Sep 9;100:108117. doi: 10.1016/j.intimp.2021.108117. Online ahead of print.ABSTRACTFPS-ZM1 is an inhibitor of the receptor for advanced glycation end products (RAGE). Nevertheless, there are few reports about its direct effects on microglial inflammation, and the underlying molecular mechanisms remain to be clarified. The present study investigated the potential effects of FPS-ZM1 on lipopolysaccharide (LPS)-mediated microglial inflammation both in vivo and in vitro, and further elucidated the possible molecular mechanisms of action. FPS-ZM1 decreased LPS-induced overproduction of interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and cyclooxygenase 2 (COX-2), in both BV-2 cells and primary microglial cells. FPS-ZM1 (10 mg/kg, i.p.) ameliorated proliferation and activation of microglia in the hippocampus of C57BL/6J mice subjected to LPS challenge (5 mg/kg, i.p.). Meanwhile, overproduction of pro-inflammatory cytokines IL-1β and TNF-α in the hippocampus was alleviated after treatment with FPS-ZM1. RNA-Sequencing (RNA-Seq) analysis showed involvement of Janus kinase (JAK)-signal transducers and activators of transcription (STAT) signaling pathway in the regulation of FPS-ZM1 on LPS-induced microglial inflammation. Further investigations demonstrated that FPS-ZM1 downregulated LPS-mediated increases in the phosphorylation levels of JAK/STAT both in vivo and in vitro. FPS-ZM1 also suppressed the nuclear translocati...
Source: International Immunopharmacology - Category: Allergy & Immunology Authors: Source Type: research