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.

Keywords: HMGB1; Hypoglycaemia; Ischemic stroke; angiogenesis; atherosclerosis; oedema.

Figure 1. HMGB1 release during ischemic events interacts with TLR-2 and TLR-4 that is expression on monocytes via the adaptor protein MyD88 and elevates serum of TNF-α, IL-1β, and IL-6 levels, which leads to cerebral vessel occlusion

Also, HMGB1 release and RAGE expression increase risk factors (HP, DM, HL), which contributes significantly to cerebral vessel occlusion during IS.

Figure 2. HMGB1 up-regulated MMP-9, which is mediated primarily through the TLR-4

HMGB1 induced cytokines such as TNF-α and IL-1β, which may promote MMP-9 up-regulation indirectly. Up-regulation of MMPs leads to increased infarct size, brain edema, and recombinant t-PA induced hemorrhage, which accelerates neurovascular substrate damage including the tight junction protein Occludin. Similarly, anti-HMGB1 mAb suppresses the activity of MMP-9, with an inhibition of the increased permeability of BBB, in ischemic brain area and reduces neuronal and glial apoptosis.

Figure 3. HMGB1 stimulates the production of IL-1, TNF-α, IL-6, and IL-8 and induces iNOS expression during ischemic brain damage

Induction of iNOS and TNF-α occurs mainly in microglia. Induction of any of the factors above produces inflammatory response and the disruption of the BBB, leading to the aggravation of brain infarction.