Abstract
SummaryAimsTo investigate the critical role of Tim‐3 in the polarization of microglia in intracerebral hemorrhage (ICH)‐induced secondary brain injury (SBI).MethodsAn in vivo ICH model was established by autologous whole blood injection into the right basal ganglia in rats. The primary cultured microglia were treated with oxygen‐hemoglobin (OxyHb) to mimic ICH in vitro. In this experiment, specific siRNA for Tim‐3 and recombinant human TIM‐3 were exploited both in vivo and in vitro.ResultsTim‐3 was increased in the brain after ICH, which mainly distributed in microglia, but not neurons and astrocytes. However, the blockade of Tim‐3 by siRNA markedly reduced secretion of inflammatory factors, neuronal degeneration, neuronal cell death, and brain edema. Meanwhile, downregulation of Tim‐3 promoted the transformation of microglia phenotype from M1 to M2 after ICH. Furthermore, upregulation of Tim‐3 can increase the interaction between Tim‐3 and Galectin‐9 (Gal‐9) and activate Toll‐like receptor 4 (TLR‐4) pathway after ICH. Increasing the expression of Tim‐3 may be related to the activation of HIF‐1α.ConclusionTim‐3 may be an important link between neuroinflammation and microglia polarization through Tim‐3/Gal‐9 and TLR‐4 signaling pathways which induced SBI after ICH.
Highlights
Intracerebral hemorrhage (ICH) is an acute central nervous system (CNS) disease with high mortality and disability, accounting for ~15% of all patients with stroke.[1]
We investigated the mechanism of secondary brain injury (SBI) after ICH through the Tim‐3/Gal‐9 signaling pathway and Toll‐like receptor 4 (TLR‐4)‐mediated in‐ flammatory responses, which were closely related to the increasing level of Tim‐3
We detected the distribution of HIF‐1α in the cytoplasm or nucleus or the whole cell after ICH, and the results showed that the level of HIF‐1α levels increased in cytoplasm and nucleus after ICH; the level of HIF‐1α decreased in cytoplasm and the level of HIF‐1α increased in nucleus after recombinant human TIM‐3 (rhTIM‐3) treatment; the level of HIF‐1α in nucleus and cytoplasm decreased after Tim‐3 siRNA treatment
Summary
Intracerebral hemorrhage (ICH) is an acute central nervous system (CNS) disease with high mortality and disability, accounting for ~15% of all patients with stroke.[1]. ICH triggers a series of complex physiological and pathological events that ul‐ timately lead to brain damage, especially in the tissues around the hematoma.[3,4] These events include the hematoma mass effect and the potential hematoma expansion, oxidative stress, inflammatory cell infiltration, cell necrosis and apoptosis.[5,6]. Tim‐3 is expressed in tissues and organs which are involved in innate immune, and specific immune response and is closely re‐ lated to the progression and outcome of various diseases.[9,10]. TLR‐4 is an essential member of the TLRs family, and it is closely related to the inflammatory response of CNS diseases.[23]. | 675 essential role in the regulation of inflammation These studies sug‐ gested that Gal‐9/Tim‐3 and TLR‐4 signaling pathways may be the potential mechanisms of neuroinflammation. We investigated the expression level and potential effects of Tim‐3 in inflammation of SBI after ICH
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