The Role And Mechanisms Of TIPE2in The Pathogenesis Of Cerebral Ischemia/Reperfusion Injury

Stroke is one of the most common vascular diseases in the cerebral nervous system and now is the second leading cause of death in the world. Despite considerable studies have demonstrated that multiple pathogenicmechanisms are involved in ischemic stroke, including inflammation, oxidative stress, excitotoxicity, calcium overload, apoptosis and disruption of the blood-brain barrier, inflammation is considered as one of the major mechanisms triggering the pathogenic actions of ischemic stroke. The inflammatory responses accompanying stroke contribute to secondary ischemic injury, which include induced microglial and astrocyte activity, increased production of cytokines, chemokines, adhesion molecules, and the infiltration of inflammatory cells into injured cerebral regions.TIPE2(TNF-a-inducible protein8-like2, or TNFAIP8L2), a recently identified protein, is a negative regulator of innate and adaptive immunity, which shares considerable sequence homology with members of the tumor necrosis factor-a-inducible protein8(TNFAIP8) family. However, to date it is unclear whether the TNFAIP8family is expressed in the brain and contributes to the regulation of cerebral functions. Given the role of TIPE2on the regulation of TLR function and the link between TLRs and ischemic cerebral injury, in the present study, we used an in vivo middle cerebral artery occlusion (MCAO) model and in vitro primary cerebral cell cultures to determine the expression and functions of TIPE2in cerebral ischemia-induced injury.Our results showed that gene deficiency of Tipe2increased the cerebral volume of infarction, neurological dysfunction, inflammatory cytokines production and infiltration of inflammatory cells in mice subjected to MCAO, suggesting a protective role of TIPE2in the pathogenic processes of stroke. We further observed that TIPE2was highly induced after cerebral ischemia and demonstrate that the regulation of TIPE2expression was associated with NADPH oxidase activity. Our results indicate that TIPE2is an immuneregulator to prevent deleterious inflammatory responses after stroke. These findings for the first time demonstrate that TIPE2is involved in the pathogenesis of stroke and suggest that TIPE2may play an essential role for a signal transduction pathway that links inflammatory immune response to specific conditions after cerebral ischemia.