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posted on 2018-03-14, 04:07 authored by 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

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.

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