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

Abstract

FPS-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 translocation of transcription factor STAT1/3/5 in BV-2 cells. In addition, inhibition of JAK/STAT signaling pathway had an anti-inflammatory effect similar to FPS-ZM1 treatment. Taken together, our results verified the inhibitory effects of FPS-ZM1 against LPS-stimulated microglial inflammation, and for the first time demonstrated such anti-inflammatory activities on microglia are associated with regulation of JAK/STAT signaling pathway both in vivo and in vitro, which may shed new light on the pharmacological mechanisms of FPS-ZM1 against microglial inflammation.

• Authors: Lan Wang, Danfeng Zhao, Huan Wang, Lele Wang, Xiaohui Liu, Haiyan Zhang
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 100 Pg. 108117 (Nov 2021) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 34509933 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• Benzamides
• FPS-ZM1
• Inflammation Mediators
• Interleukin-1beta
• Interleukin-6
• Lipopolysaccharides
• NF-kappa B
• Receptor for Advanced Glycation End Products
• STAT Transcription Factors
• Tumor Necrosis Factor-alpha
• Nitric Oxide Synthase Type II
• Cyclooxygenase 2
• Janus Kinases

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Benzamides (pharmacology)
• Cell Line
• Cyclooxygenase 2 (metabolism)
• Hippocampus (metabolism)
• Inflammation (drug therapy)
• Inflammation Mediators (metabolism)
• Interleukin-1beta (metabolism)
• Interleukin-6 (metabolism)
• Janus Kinases (metabolism)
• Lipopolysaccharides
• Mice
• Mice, Inbred C57BL
• Microglia (drug effects, metabolism)
• NF-kappa B (metabolism)
• Nitric Oxide Synthase Type II (metabolism)
• Receptor for Advanced Glycation End Products (metabolism)
• STAT Transcription Factors (metabolism)
• Signal Transduction (drug effects)
• Tumor Necrosis Factor-alpha (metabolism)