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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.
Highlights
High-mobility group (HMG) proteins are non-histone nuclear proteins
We showed that High-mobility group nucleosome-binding protein 1 (HMGN1) functions as an endogenous TLR4 ligand that, on the one hand, stimulates acute cytokine production and, on the other hand, induces tolerance in monocytes through a Sirtuin-1dependent mechanism
We first examined the capability of HMGN1 to induce proinflammatory cytokine production in human Peripheral Blood Mononuclear Cells (PBMCs)
Summary
High-mobility group (HMG) proteins are non-histone nuclear proteins. They bind to nucleosomes and regulate chromosome architecture and gene transcription [1]. Upon cell stimulation or under stress situations, such as mechanical change and tissue damage, HMG proteins can be either released or excreted into the extracellular space [2]. HMGB1 is the best-characterized HMG-family protein: it is released from injured or activated innate immune cells [1], it stimulates cytokine and chemokine production [3], it can induce dendritic cell activation [4], and it is chemotactic and functions an alarmin. High-mobility group nucleosome-binding protein 1 (HMGN1) belongs to the HMG N family but it exhibits no homology to HMGB1. The functions of HMGN1 were mainly related to its nuclear
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