Pivotal neuroinflammatory and therapeutic role of high mobility group box 1 in ischemic stroke

Abstract

Stroke is a major cause of mortality and disability worldwide. Stroke is a frequent and severe neurovascular disorder. The main cause of stroke is atherosclerosis, and the most common risk factor for atherosclerosis is hypertension. Therefore, prevention and treatment of stroke are crucial issues in humans. High mobility group box 1 (HMGB1) is non-histone nuclear protein that is currently one of the crucial proinflammatory alarmins in ischemic stroke (IS). It is instantly released from necrotic cells in the ischemic core and activates an early inflammatory response. HMGB1 may signal via its putative receptors, such as receptor for advanced glycation end products (RAGE), toll-like receptors (TLRs) as well as matrix metalloproteinase (MMP) enzymes during IS. These receptors are expressed in brain cells. Additionally, brain-released HMGB1 can be redox modified in the circulation and activate peripheral immune cells. The role of HMGB1 may be more complex. HMGB1 possesses beneficial actions, such as endothelial activation, enhancement of neurite outgrowth, and neuronal survival. HMGB1 may also provide a novel link for brain-immune communication leading to post-stroke immunomodulation. Therefore, HMGB1 is new promising therapeutic intervention aimed at promoting neurovascular repair and remodeling after stroke. In this review, we look at the mechanisms of secretion of HMGB1, the role of receptors, MMP enzymes, hypoglycemia, atherosclerosis, edema, angiogenesis as well as neuroimmunological reactions and post-ischemic brain recovery in IS. We also outline therapeutic roles of HMGB1 in IS.

Danger signals in stroke and their role on microglia activation after ischemia

“… 27 It is secreted by activated astrocytes and microglia, and stimulates the release of interleukin (IL)-1, TNFα, IL-6 and IL-8, as well as inducible nitric oxide synthase (iNOS) expression. 28 – 31 An increased vascular and blood–brain barrier permeability is observed. 31 Moreover, matrix metalloproteinase 9 (MMP-9) is upregulated by HMGB1 via TLR4 and its induced cytokines as TNFα or IL-1β mediating cellular death after ischemic stroke.…”

“… 28 – 31 An increased vascular and blood–brain barrier permeability is observed. 31 Moreover, matrix metalloproteinase 9 (MMP-9) is upregulated by HMGB1 via TLR4 and its induced cytokines as TNFα or IL-1β mediating cellular death after ischemic stroke. 31 A maturation process of the passively released protein in the blood circulation to a cytokine-stimulating isoform has been described.…”

The role of Toll-like receptor signaling pathways in cerebrovascular disorders: the impact of spreading depolarization

“…HMGB1signals via TLR2 and TLR4 signaling activate the NF-κB pathway and induce a proinflammatory response [110]. Several studies have shown that plasma levels of HMGB1 increase in ischemic stroke and correlate with poor outcome [111][112][113].…”

The Therapeutic Potential of Resveratrol in Gliomas

“…High mobility group box 1 (HMGB1) is a non-histone, DNA-binding protein that primarily dwells in the nucleus and is associated with the alteration of transcription, DNA repair and chromatin steadiness (108,109,132). Studies have shown that the translocation of HMGB1 out of the nucleus is initiated by it acetylation resulting in its relocation.…”