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

Author:

Arts, Rob J W

Huang, Po-Kai

Yang, De

Joosten, Leo A B

van der Meer, Jos W M

Oppenheim, Joost

Netea, Mihai G

Cheng, Shih-Chin
Author Address

Department of Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands., College of Life Science, Institute of Molecular Medicine, National Tsing Hua University, Hsinchu City, Taiwan., Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institue at Frederick, Frederick, MD, United States., Human Genomics Laboratory, Craiova University of Medicine and Pharmacy, Craiova, Romania.,

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 calledalarmin). 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 deacetylationviaSirtuin-1. In addition, HMGN1 pre-challenge of mice also downregulated TNF production similar to LPS-induced tolerancein 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.

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