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

Front Immunol. 2018 Mar 14;9:526. doi: 10.3389/fimmu.2018.00526. eCollection 2018.


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.

Keywords: endotoxin tolerance; high-mobility group nucleosome-binding protein 1; macrophages; sirtuin-1; sterile inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytokines / blood
  • Female
  • HMGN1 Protein / immunology*
  • Humans
  • Immune Tolerance
  • Immunity, Innate
  • Leukocytes, Mononuclear / immunology*
  • Ligands
  • Mice, Inbred C57BL
  • Sirtuin 1 / immunology*
  • Toll-Like Receptor 4 / immunology*


  • Cytokines
  • HMGN1 Protein
  • Ligands
  • Toll-Like Receptor 4
  • Sirtuin 1