High-Mobility Group Nucleosome-Binding Protein 1 as Endogenous Ligand Induces Innate Immune Tolerance in a TLR4-Sirtuin-1 Dependent Manner in Human Blood Peripheral Mononuclear Cells

被引：11

作者：

Arts, Rob J. W. ^{[1
]}

Huang, Po-Kai ^{[2
]}

Yang, De ^{[3
]}

Joosten, Leo A. B. ^{[1
]}

van der Meer, Jos W. M. ^{[1
]}

Oppenheim, Joost J. ^{[3
]}

Netea, Mihai G. ^{[1
,4
]}

Cheng, Shih-Chin ^{[2
]}

机构：

[1] Radboud Univ Nijmegen, Med Ctr, Radboud Ctr Infect Dis, Dept Med, Nijmegen, Netherlands

[2] Natl Tsing Hua Univ, Inst Mol Med, Coll Life Sci, Hsinchu, Taiwan

[3] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA

[4] Craiova Univ Med & Pharm, Human Genom Lab, Craiova, Romania

来源：

FRONTIERS IN IMMUNOLOGY | 2018年 / 9卷

关键词：

high-mobility group nucleosome-binding protein 1; endotoxin tolerance; sterile inflammation; sirtuin-1; macrophages; HMGB1; ALARMIN; LIPOPOLYSACCHARIDE; INFLAMMATION; CONTRIBUTES; DNA;

D O I：

10.3389/fimmu.2018.00526

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

High-mobility group nucleosome-binding protein 1 (HMGN1) functions as a non-histone chromatin-binding protein in the cell nucleus. However, extracellular HMGN1 acts as an endogenous danger-associated inflammatory mediator (also called alarmin). We demonstrated that HMGN1 not only directly stimulated cytokine production but also had the capacity to induce immune tolerance by a TLR4-dependent pathway, similar to lipopolysaccharide (LPS)-induced tolerance. HMGN1-induced tolerance was accompanied by a metabolic shift associated with the inhibition of the induction of Warburg effect (aerobic glycolysis) and histone deacetylation via Sirtuin-1. In addition, HMGN1 pre-challenge of mice also downregulated TNF production similar to LPS-induced tolerance in vivo. In conclusion, HMGN1 is an endogenous TLR4 ligand that can induce both acute stimulation of cytokine production and long-term tolerance, and thus it might play a modulatory role in sterile inflammatory processes such as those induced by infection, trauma, or ischemia.

引用

页数：9