Abstract
BackgroundAn acute and drastic inflammatory response characterized by the production of inflammatory mediators is followed by stroke, including SAH. Overactivation of microglia parallels an excessive inflammatory response and worsened brain damage. Previous studies indicate that TSG-6 has potent immunomodulatory and anti-inflammatory properties. This study aimed to evaluate the effects of TSG-6 in modulating immune reaction and microglial phenotype shift after experimental SAH.MethodsThe SAH model was established by endovascular puncture method for Sprague–Dawley rats (weighing 280–320 g). Recombinant human protein and specific siRNAs for TSG-6 were exploited in vivo. Brain injury was assessed by neurologic scores, brain water content, and Fluoro-Jade C (FJC) staining. Microglia phenotypic status was evaluated and determined by Western immunoblotting, quantitative real-time polymerase chain reaction (qPCR) analyses, flow cytometry, and immunofluorescence labeling.ResultsSAH induced significant inflammation, and M1-dominated microglia polarization increased expression of TSG-6 and neurological dysfunction in rats. rh-TSG-6 significantly ameliorated brain injury, decreased proinflammatory mediators, and skewed microglia towards a more anti-inflammatory property 24-h after SAH. While knockdown of TSG-6 further induced detrimental effects of microglia accompanied with more neurological deficits, the anti-inflammation effects of rh-TSG-6 were associated with microglia phenotypic shift by regulating the level of SOCS3/STAT3 axis.ConclusionsTSG-6 exerted neuroprotection against SAH-induced EBI in rats, mediated in part by skewing the balance of microglial response towards a protective phenotype, thereby preventing excessive tissue damage and improving functional outcomes. Our findings revealed the role of TSG-6 in modulating microglial response partially involved in the SOCS3/STAT3 pathway and TSG-6 may be a promising therapeutic target for the treatment of brain injury following SAH.
Highlights
An acute and drastic inflammatory response characterized by the production of inflammatory mediators is followed by stroke, including Subarachnoid hemorrhage (SAH)
No significant differences on TSG-6 messenger RNA (mRNA) expression and protein abundance were found in different timepoints in sham We found that there was no statistical difference of TSG-6 detected variables among sham groups at each time (Additional file 1A, B)
Consistent with the findings of previous study [44], our study showed that, after induction of SAH, augmented microglia were identified by the panorama of brain slices and more strikingly elevated proinflammatory genes compared to anti-inflammatory genes within 72 h after SAH was revealed by PCR. rh-TSG-6 treatment significantly suppressed the prevailing M1
Summary
An acute and drastic inflammatory response characterized by the production of inflammatory mediators is followed by stroke, including SAH. Previous studies indicate that TSG-6 has potent immunomodulatory and anti-inflammatory properties. This study aimed to evaluate the effects of TSG-6 in modulating immune reaction and microglial phenotype shift after experimental SAH. Healthy people can harbor intracranial aneurysms noted in occasional examination or emerging with several symptoms, otherwise detected with SAH onset [2, 3]. SAH is usually catastrophic because there exists no effective therapy applied in concomitant brain injury [4]. Early brain injury (EBI) and delayed cerebral ischemia (DCI) represent the main effects of SAH at two stages, and neuroprotection and anti-vasospasm are the most studied targets in numerous research [5, 6]. Nimodipine has been widely used in clinical application and has proven effective in the treatment of SAH [8]
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