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.
Highlights
Animals were subjected to middle cerebral artery occlusion (MCAO) for 30, 60, 90, or 120 min using a suture as previously described (Fig. 1a, b)[19], and the amounts of High-mobility group box 1 (HMGB1) in cerebrospinal fluid (CSF) or serum were examined at 1 day post-MCAO
While HMGB1 levels in penumbra increased depending on stroke severity, they decreased in infarct cores due to an acute and massive neuronal cell death in cortices of the ipsilateral hemisphere (Fig. 1c, g–i)
When the same amount of LPS was administered to MCAO animals, mean infarct volumes measured at 2 days post-MCAO were elevated by 27.1 ± 6.5% (n = 7, p < 0.01) compared to that in treatment-naïve MCAO controls (Fig. 2b, c), indicating that LPS injection to post-MCAO animals aggravated ischemic damage
Summary
One-third of stroke patient deaths in hospitals can be attributable to post-stroke infection (PSI), especially respiratory and urinary tract infections[1,2]. Numerous mechanisms may underlie increasing risk of PSIs, including the direct consequences of stroke, such as inflammatory activation and brain-induced immune depression, along with indirect factors associated with stroke, such as advanced age and comorbidity[3,4]. Aggravations of brain-specific inflammation and systemic inflammation appear to play critical roles in increasing the frequency of PSI and in worsening functional outcomes of stroke patients[5]. HMGB1 was reported to act as an endogenous danger-associated molecular pattern (DAMP)[7] after being released by necrotic cells or actively secreted by macrophages/monocytes into the extracellular environment, thereby triggering and amplifying inflammatory processes[8,9,10].
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