Hepatocyte-specific high-mobility group box 1 deletion worsens the injury in liver ischemia/reperfusion: A role for intracellular high-mobility group box 1 in cellular protection

Abstract

High-mobility group box 1 (HMGB1) is an abundant chromatin-associated nuclear protein and released into the extracellular milieu during liver ischemia-reperfusion (I/R), signaling activation of proinflammatory cascades. Because the intracellular function of HMGB1 during sterile inflammation of I/R is currently unknown, we sought to determine the role of intracellular HMGB1 in hepatocytes after liver I/R. When hepatocytespecific HMGB1 knockout (HMGB1-HC-KO) and control mice were subjected to a nonlethal warm liver I/R, it was found that HMGB1-HC-KO mice had significantly greater hepatocellular injury after I/R, compared to control mice. Additionally, there was significantly greater DNA damage and decreased chromatin accessibility to repair with lack of HMGB1. Furthermore, lack of hepatocyte HMGB1 led to excessive poly(ADP-ribose)polymerase 1 activation, exhausting nicotinamide adenine dinucleotide and adenosine triphosphate stores, exacerbating mitochondrial instability and damage, and, consequently, leading to increased cell death. We found that this was also associated with significantly more oxidative stress (OS) in HMGB1-HC-KO mice, compared to control. Increased nuclear instability led to a resultant increase in the release of histones with subsequently more inflammatory cytokine production and organ damage through activation of Toll-like receptor 9. Conclusion: The lack of HMGB1 within hepatocytes leads to increased susceptibility to cellular death after OS conditions.

High Mobility Group Box 1 (HMGB1) Phenotypic Role Revealed with Stress

“…This result suggests that HMGB1 available in trans is sufficient to provide its regulatory function to knockout cells, or alternatively, that it is redundant without stress within individual cells for basal metabolic functions. In contrast, an aberrant response to targeted stress is observed in the liver, pancreas or myeloid cells, consistent with a protective role for HMGB1 (7)(8)(9) as well as unpublished results of studies on natural killer and dendritic cells. Interestingly, a recent study from RF Schwabe and colleagues indicates that HMGB1 is not required for autophagy, mitochondrial function and organ function in vivo (10).…”

The HMGB1/RAGE axis triggers neutrophil-mediated injury amplification following necrosis

“…In the healthy organism, HMGB1 functions as a DNA-binding protein that, without apparent sequence specificity, induces bends in the DNA helix, allowing interactions between DNA and proteins such as p53, NF-κB, homeobox-containing proteins, recombinases, and steroid hormone receptors (14). Although mice with global Hmgb1 deletion die shortly after birth (15), several recent studies have shown that intracellular HMGB1 is not required for cell homeostasis and organ function in the healthy adult organism (16)(17)(18). During tissue injury or sepsis, HMGB1 is passively released from necrotic cells and actively secreted by inflammatory cells, with signature posttranslational modifications that are characteristic of the respective release mechanism (19).…”

Serum Amyloid A Stimulates PKR Expression and HMGB1 Release Possibly through TLR4/RAGE Receptors

“…However, caution should be exercised when using gene knockout approaches to evaluate the pathogenic roles of any particular mediators that are still critically needed for maintaining beneficial physiological functions. For instance, despite the well-established pathogenic role of HMGB1 in infection-and injuryelicited inflammatory diseases (60,61), the disruption of HMGB1 expression adversely renders animals more susceptible to infectious (62) or injurious insults (63,64), reinforcing the dramatically distinct roles of HMGB1 in health and disease (65). Similarly, in an animal model of dextran sodium sulfate (DSS)-induced colitis, SAA1/2 knockout mice appeared to be more susceptible to colitis, possibly because the intestinal epithelia-derived SAAs are still critically needed for bactericidal activities (34).…”