Alarmin HMGB1 induces systemic and brain inflammatory exacerbation in post-stroke infection rat model

Abstract

Post-stroke infection (PSI) is known to worsen functional outcomes of stroke patients and accounts to one-third of stroke-related deaths in hospital. In our previous reports, we demonstrated that massive release of high-mobility group box protein 1 (HMGB1), an endogenous danger signal molecule, is promoted by N-methyl-d-aspartic acid-induced acute damage in the postischemic brain, exacerbating neuronal damage by triggering delayed inflammatory processes. Moreover, augmentation of proinflammatory function of lipopolysaccharides (LPS) by HMGB1 via direct interaction has been reported. The aim of this study was to investigate the role of HMGB1 in aggravating inflammation in the PSI by exacerbating the function of LPS. PSI animal model was produced by administrating a low-dose LPS at 24 h post-middle cerebral artery occlusion (MCAO). Profound aggravations of inflammation, deterioration of behavioral outcomes, and infarct expansion were observed in LPS-injected MCAO animals, in which serum HMGB1 surge, especially disulfide type, occurred immediately after LPS administration and aggravated brain and systemic inflammations probably by acting in synergy with LPS. Importantly, blockage of HMGB1 function by delayed administrations of therapeutic peptides known to inhibit HMGB1 (HMGB1 A box, HPep1) or by treatment with LPS after preincubation with HMGB1 A box significantly ameliorated damages observed in the rat PSI model, demonstrating that HMGB1 plays a crucial role. Furthermore, administration of Rhodobacter sphaeroides LPS, a selective toll-like receptor 4 antagonist not only failed to exert these effects but blocked the effects of LPS, indicating its TLR4 dependence. Together, these results indicated that alarmin HMGB1 mediates potentiation of LPS function, exacerbating TLR4-dependent systemic and brain inflammation in a rat PSI model and there is a positive-feedback loop between augmentation of LPS function by HMGB1 and subsequent HMGB1 release/serum. Therefore, HMGB1 might be a valuable therapeutic target for preventing post-stroke infection.

Oxidation of HMGB1 Is a Dynamically Regulated Process in Physiological and Pathological Conditions

“…In our study, we showed that it is possible to perform Western blot assays to analyse the expression of HMGB1 redox isoforms both at cell and tissue levels. Other studies reported the detection of HMGB1 redox isoforms in serum and plasma by Western blot assay (31,32), showing that this method can also be applied to extracellular fluids. Western blot has a wide range of applications in the clinic, such as the application of medical diagnosis for FIGURE 5 | Redox modulation of HMGB1 in spleen and in drug-intoxicated liver.…”

Ginsenoside-Rb1 for Ischemic Stroke: A Systematic Review and Meta-analysis of Preclinical Evidence and Possible Mechanisms

“…Once there are infections or tissue injuries, HMGB1 can be upregulated by immune cells or necrotic cells (Lotze and Tracey, 2005). In cerebral ischemia/reperfusion processes, it triggers delayed inflammation and exacerbates neuron damage (Kim et al, 2018). On the other hand, the NF-kB family, consisting of transcription factors, and its associated signaling pathway play a complex but crucial role in the regulation of immune response (Tilborghs et al, 2017).…”

Beyond the Brain: The Systemic Pathophysiological Response to Acute Ischemic Stroke

“…One study confirmed overstimulation of cardiac sympathetic innervation using the catecholamine synthesis rate-limiting enzyme tyrosine hydrolase. 7 Sympathetic hyperstimulation also blunts vagal influence, as confirmed in stroke patients via heart rate variability testing. 61 HPA activation and hypothalamic paraventricular nucleus output also prompted cardiac arrhythmias and impaired cardiac output in rat models.…”

“…6 AIS research has historically focused on these central nervous system (CNS) interventions to reduce infarct volume and address neuronal viability. More re-cently, however, detrimental effects of AIS on the heart 7 and immune system 8 have gained popularity. Indeed, medical complications following AIS such as pneumonia are strong predictors of mortality and functional outcome.…”