CHIP ameliorates cerebral ischemia-reperfusion injury by attenuating necroptosis and inflammation

Abstract

Blood reperfusion of ischemic cerebral tissue may cause cerebral ischemia-reperfusion (CIR) injury. Necroptosis and inflammation have been demonstrated to be involved in the disease-related process of CIR injury. The E3 ubiquitin ligase carboxyl terminus of Hsp70-interacting protein (CHIP) can modulate multiple cellular signaling processes, including necroptosis and inflammation. Numerous studies have demonstrated the neuroprotective effects of CHIP on multiple central nervous system (CNS) diseases. However, the effects of CHIP on CIR injury have not been fully explored. We hypothesize that CHIP can exert neuroprotective effects by attenuating necroptosis and inflammation during CIR injury. In the present study, adult wild-type (WT) C57BL/6 mice and CHIP knock-in (KI) mice with a C57BL/6 background and CHIP overexpression in neural tissue underwent middle cerebral artery occlusion (MCAO) surgery to simulate CIR onset. Our data indicated that CHIP expression in the peri-infarct tissue was markedly increased after MCAO surgery. Compared with WT mice, CHIP KI mice significantly improved neurological deficit scores, decreased cerebral infarct volume, and attenuated brain edema and neuronal damage. Meanwhile, CHIP overexpression attenuated necroptosis and inflammation induced by MCAO surgery. These findings indicated that overexpression of CHIP might exert neuroprotective effects by attenuating necroptosis and inflammation during CIR injury, and increasing CHIP levels may be a potential strategy in cerebrovascular disease therapy.

CHIP ameliorates neuronal damage in H2O2-induced oxidative stress in HT22 cells and gerbil ischemia

“…Pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, were significantly increased in the hippocampus after ischemia induction, and Tat-CHIP attenuated the increase in pro-inflammatory cytokine release, suggesting the anti-inflammatory potential of Tat-CHIP in ischemic damage. This result was consistent with that of a previous study showing that CHIP overexpression reduced IL-1β, IL-6, and TNF-α levels in brain tissues after middle cerebral artery occlusion 39 . Transient forebrain ischemia depleted the GSH and its redox enzymes in the hippocampus, which is the main causes of neuronal death 55 .…”

“…Administration of Tat-CHIP dose-dependently ameliorated ischemia-induced hyperlocomotion 1 day after ischemia induction and improved neuronal survival in the CA1 region 4 days after ischemia induction based on immunohistochemical staining for NeuN. Several studies have demonstrated that overexpression of CHIP protects neurons against ischemic damage induced by middle cerebral artery occlusion 23,39 . CHIP overexpression attenuates cellular damage in the heart after cardiac ischemia 46 .…”

“…CHIP is believed to be a key player in neurological disorders because it has E3 ubiquitin ligase activity to remove damaged or toxic proteins, and is highly expressed in the brain tissue 14 , 38 . CHIP levels are increased in mouse peri-infarct tissues after middle cerebral artery occlusion 39 and in postmortem samples from ischemic patients 21 . In the present study, we synthesized a Tat-CHIP fusion protein to facilitate the crossing of the blood–brain barrier and to deliver the proteins into neurons because gene delivery is difficult in clinical practice.…”

“…CHIP is believed to be a key player in neurological disorders because it has E3 ubiquitin ligase activity to remove damaged or toxic proteins, and is highly expressed in the brain tissue 14,38 . CHIP levels are increased in mouse peri-infarct tissues after middle cerebral artery occlusion 39 and in postmortem samples from ischemic patients 21 .…”

Identification of programmed cell death-related gene signature and associated regulatory axis in cerebral ischemia/reperfusion injury

“…Increasing studies have suggested that necroptosis participates in the pathogenesis of various diseases including ischemia stroke. Studies have also indicated that the inhibition of necroptosis can exert neuroprotective effects after cerebral I/R in mice by reducing cerebral infarct volume and improving motor and cognitive function ( Deng et al, 2019 ; Yao et al, 2021 ). Pyroptosis is a kind of inflammatory programmed cell death that is characterized by rapid plasma-membrane rupture and the release of proinflammatory intracellular contents as well as cytokines ( Yu et al, 2021 ).…”