High-Mobility Group Protein Box-1 and its Relevance to Cerebral Ischemia

Abstract

High-mobility group box-1 (HMGB1) was originally identified as a ubiquitously expressed, abundant, nonhistone DNA-binding protein. It has well-established functions in the maintenance of nuclear homeostasis. The HMGB1 can either be passively released into the extracellular milieu in response to necrotic signals or actively secreted in response to inflammatory signals. Extracellular HMGB1 interacts with receptors, including those for advanced glycation endproducts (RAGEs) as well as Toll-like receptor 2 (TLR2) and TLR4. The HMGB1 functions in a synergistic manner with other proinflammatory mediators and acts as a potent proinflammatory cytokine-like factor that contributes to the pathogenesis of diverse inflammatory and infectious disorders. Numerous reports point to HMGB1 as a novel player in the ischemic brain. This review provides an appraisal of the emerging roles of HMGB1 in cerebral ischemia injury, highlighting the relevance of HMGB1-blocking agents as potent therapeutic tools for neuroprotection.

A Combination of Remote Ischemic Perconditioning and Cerebral Ischemic Postconditioning Inhibits Autophagy to Attenuate Plasma HMGB1 and Induce Neuroprotection Against Stroke in Rat

“…It has been reported that cerebral ischemia can upregulate serum HMGB1 to stimulate the release of TNFα, IL-6, and other inflammatory factors to induce inflammation, which will contribute to cerebral ischemic injury (Yang et al 2010). Certain HMGB1 inhibitors or some physical methods can attenuate injuries caused by cerebral ischemia reperfusion or neonatal hypoxic-ischemic encephalopathy (Nakamura et al 2013;Rickenbacher et al 2014;Wang et al 2012).…”

Necrotic cell-derived high mobility group box 1 attracts antigen-presenting cells but inhibits hepatocyte growth factor-mediated tropism of mesenchymal stem cells for apoptotic cell death

“…32 It recruits monocytes/ macrophages and DC to sites of tissue damage or infection and causes their activation, thereby mediating sterile, tissueinjury-driven as well as pathogen-driven inflammation and the initiation of adaptive immune responses. 25,33 Although the inflammatory processes initiated by HMGB1 appear to be detrimental to tissue regeneration, 25,34 pro-angiogenic activities of HMGB1 35 as well as recruitment of stem and progenitor cells 36,37 may have beneficial effects after tissue damage.…”

The Complexity of the Innate Immune System Activation in Stroke Pathogenesis

“…In addition, DAMPs can engage TLRs to induce and amplify the inflammatory response. For example, TLR2 and TLR4 can mediate NF-κB activation initiated by the high-mobility group box-1 (HMGB1) protein (Park et al, 2006), a nonhistone nuclear protein passively released by necrotic cells that mediates innate immune activation and tissue injury after stroke (Yang et al, 2010).…”