Negative regulation of glial Tim-3 inhibits the secretion of inflammatory factors and modulates microglia to antiinflammatory phenotype after experimental intracerebral hemorrhage in rats.

Aims To investigate the critical role of Tim-3 in the polarization of microglia in intracerebral hemorrhage (ICH)-induced secondary brain injury (SBI). Methods An 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. Results Tim-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-1 alpha. Conclusion Tim-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.