Preconditioning With High Mobility Group Box 1 (HMGB1) Induces Lipoteichoic Acid (LTA) Tolerance

Abstract

High mobility group box chromosomal protein 1 (HMGB1) is a DNA binding protein that exhibits pro-inflammatory properties when present in the extracellular compartment. Putative receptors for HMGB1 include Toll-like receptor (TLR) 4, TLR2 and the receptor for advanced glycation end products (RAGE). We tested the hypothesis that extracellular HMGB1 can induce tolerance to the bacterial product, lipoteichoic acid (LTA). Pretreatment of human monocyte-like THP-1 cells with 1 μg/ml HMGB1 18 h before exposure to LTA (10 μg/ml) decreased secretion of TNF, NF-κB DNAbinding, and degradation of IκBα. Denaturation of HMGB1 with boiling water or co-incubation with anti-HMGB1 antibody abrogated the induction of tolerance to LTA. In contrast, co-incubation with polymyxin B failed to diminish HMGB1-induced tolerance to LTA. These findings support the view that the induction of LTA tolerance by HMGB1 was not due to LPS contamination. Bone marrowderived macrophages obtained from C57Bl/6 wild-type and RAGE-deficient mice became LTAtolerant following HMGB1 exposure ex vivo. We were unable to demonstrate LTA tolerance in TLR2 and TLR4-deficient macrophages, as they are hyporesponsive to LTA. These findings suggest that extracellular HMGB1 induces LTA tolerance, and RAGE receptor is not required for this induction.

HMGB1 in health and disease

“…In addition, HMGB1 has the ability to inhibit macrophage-mediated efferocytosis, which prevents macrophages from clearing dead cells and DAMP release (Friggeri et al, 2010; Liu et al, 2008a). Interestingly, pretreatment with HMGB1 leads to endotoxin and lipoteichoic acid tolerance in bone marrow-derived macrophages and the acute monocytic leukemia cell line THP-1 by downregulation NF-KB activity (Aneja et al, 2008; Robert et al, 2010). However, RAGE is required for HMGB1-mediated endotoxin tolerance, whereas TLR2 and TLR4 are required for HMGB1-mediated lipoteichoic acid tolerance (Aneja et al, 2008; Robert et al, 2010).…”

“…Interestingly, pretreatment with HMGB1 leads to endotoxin and lipoteichoic acid tolerance in bone marrow-derived macrophages and the acute monocytic leukemia cell line THP-1 by downregulation NF-KB activity (Aneja et al, 2008; Robert et al, 2010). However, RAGE is required for HMGB1-mediated endotoxin tolerance, whereas TLR2 and TLR4 are required for HMGB1-mediated lipoteichoic acid tolerance (Aneja et al, 2008; Robert et al, 2010). More recently, endogenous HMGB1 has been found to be required in endotoxin tolerance in macrophages (Li et al, 2013d), and conditional knockout of HMGB1 in macrophages was found to cause animal death in response to endotoxemia and bacterial infection (Yanai et al, 2013).…”

PI3K/Akt signaling pathway involved in cardioprotection of preconditioning with high mobility group box 1 protein during myocardial ischemia and reperfusion

“…Previous study showed that HMGB1 preconditioning could induce lipoteichoic acid tolerance and LPS tolerance. These results indicated that HMGB1 preconditioning may also provide a HMGB1 tolerance and cardioprotection [5,6].…”

The Role of High Mobility Group Box 1 in Innate Immunity

“…These HMGB1-tolerant macrophages exhibit down regulation of intracellular signaling pathways, which subsequently decrease the activity of proinflammatory gene transcription and production of cytokines, such as TNF-α, IL-6, and IL-1β 90. Similarly, HMGB1 also induces LTA tolerance, but does not require RAGE for its induction 91. Further investigation is necessary to identify whether TLR4 or other receptors are involved in the induction of tolerance by preconditioning with HMGB1.…”