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.

Abstract

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.

• Authors: Rob J W Arts, Po-Kai Huang, De Yang, Leo A B Joosten, Jos W M van der Meer, Joost J Oppenheim, Mihai G Netea, Shih-Chin Cheng
• Journal: Frontiers in immunology (Front Immunol) Vol. 9 Pg. 526 ( 2018) ISSN: 1664-3224 [Print] Switzerland
• PMID: 29593748 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• 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)