H4 Receptor Inhibits Lipopolysaccharide-induced NF-κB Activation by Interacting with Tumor Necrosis Factor Receptor-Associated Factor 6

Yanfeng Shan; Yining Gao; Li Zhang; Lili Ma; Yuwen Shi; Xia Liu

doi:10.1016/j.neuroscience.2018.11.050

H4 Receptor Inhibits Lipopolysaccharide-induced NF-κB Activation by Interacting with Tumor Necrosis Factor Receptor-Associated Factor 6

Neuroscience. 2019 Feb 1:398:113-125. doi: 10.1016/j.neuroscience.2018.11.050. Epub 2018 Dec 5.

Authors

Yanfeng Shan¹, Yining Gao², Li Zhang², Lili Ma², Yuwen Shi², Xia Liu³

Affiliations

¹ Department of Pathophysiology, Medical College of Nantong University, 19 Qixiu Street, Nantong 226001, Jiangsu Province, China; Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College of Nantong University, 19 Qixiu Street, Nantong 226001, Jiangsu Province, China.
² Department of Pathophysiology, Medical College of Nantong University, 19 Qixiu Street, Nantong 226001, Jiangsu Province, China.
³ Department of Pathophysiology, Medical College of Nantong University, 19 Qixiu Street, Nantong 226001, Jiangsu Province, China. Electronic address: liuxia_fd@ntu.edu.cn.

PMID: 30528857
DOI: 10.1016/j.neuroscience.2018.11.050

Abstract

Microglia, the resident immune cells of the central nervous system (CNS), are activated at the beginning of the inflammatory response and induce detrimental neuroinflammation by producing excessive pro-inflammatory cytokines. Nuclear factor kappa B (NF-κB) signaling facilitates the onset of microglia activation. However, the molecular mechanisms underlying the negative regulation of NF-κB remain to be fully elucidated. In the present study, our results indicated that H4R expression increased in a rat model of lipopolysaccharide (LPS)-induced CNS inflammation. Knockdown of H4R in microglia HAPI cells enhanced the production of cytokines following LPS stimulation. Co-immunoprecipitation experiments further revealed an interaction between H4R and tumor necrosis factor receptor-associated factor 6 (TRAF6) in microglia, which was verified both in vivo and in vitro. Our experimental results support our hypothesis that H4R interacts with TRAF6 to inhibit the release of inflammatory cytokines in LPS-induced microglia cells by decreasing TRAF6-mediated ubiquitination of K63. These findings provide theoretical and experimental evidence regarding the role of H4R in the microglia inflammatory response, which may aid in the development of novel treatments for inflammation.

Keywords: NF-κB signaling pathway; histamine H4 receptor (H4R); lipopolysaccharides (LPS); microglia; tumor necrosis factor receptor-associated factor 6 (TRAF6).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Movement / physiology
Cell Proliferation / physiology
HEK293 Cells
Humans
Inflammation / metabolism*
Lipopolysaccharides
Male
Microglia / immunology*
NF-kappa B / metabolism*
Rats, Sprague-Dawley
Receptors, Histamine H4 / metabolism*
TNF Receptor-Associated Factor 6 / metabolism*

Substances

Lipopolysaccharides
NF-kappa B
Receptors, Histamine H4
TNF Receptor-Associated Factor 6