The Inflammatory Reaction Of Tim-3 In Early Brain Injury After Subarachnoid Hemorrhage In Rats And The Relevant Mechanism

Background:Inflammation is known to play an important role in early brain injury(EBI)after subarachnoid hemorrhage(SAH).T cell immunoglobulin and mucin domain-3(Tim-3)has emerged as a critical regulator of adaptive and innate immune responses,and has been identified to play a vital role in certain inflammatory diseases;however,the effect of Tim-3 on inflammatory responses in EBI following SAH is unclear.The purpose of this study was to investigate the role of tim-3 in the early brain injury after subarachnoid hemorrhage and its related mechanismMethods:A Sprague-Dawley rat SAH model was established using the endovascular puncture method.Tim-3 adeno-associated virus(AAV),Tim-3 small interfering RNA(siRNA),and N-[5-(2-Furanyl)-1,3,4-oxadiazol-2-yl]-N'-(2-pyridinylmethyl)urea(NK252)were injected intracerebroventricularly and brain injury was assessed by neurologic scores,brain water content,blood-brain barrier permeability and TUNEL staining.Tim-3,Nuclear factor(ery thro id-derived 2)-like 2(Nrf2),High mobility group protein B1(HMGB1)protein were analyzed by immunofluorescence,immunohistochemistry,western blotting,the transcript levels of Tim-3 was detected by quantitative real-time polymerase chain reaction.Pro-inflammatory cytokines,such as tumor necrosis factor alpha,interleukin(IL)-1 beta,IL-17,and IL-18,were measured by enzyme-linked immunosorbent assays.Results:SAH induced a significant inflammatory response and significantly increased Tim-3 expression.Tim-3-AAV administration aggravated brain edema,blood-brain barrier permeability,and neurological dysfunction;significantly inhibited Nrf2 expression;and increased HMGB1 expression and secretion of pro-inflammatory cytokines,such as tumor necrosis factor alpha(TNF-?),interleukin(IL)-1 beta,IL-17,and IL-18.Tim-3 siRNA or NK252 administration abolished the pro-inflammatory effects of Tim-3.Conclusions:Results indicate a function for Tim-3 as a molecular player that links neuroinflammation and brain damage after SAH.We reveal that it can aggravate the neuroinflammation of early brain injury after SAH by inhibiting Nrf2/HMGB1 signaling pathway in rats.