Loss of Wip1 aggravates brain injury after ischaemia/reperfusion by overactivating microglia

Abstract

Background and purposeThe inflammatory response mediated by microglia/macrophages is closely related to cerebral ischaemia/reperfusion injury. Wild-type p53-induced protein phosphatase 1 (Wip1), a serine/threonine phosphatase, is expressed in various tissues. A growing number of reports have suggested that Wip1 is a negative regulator of inflammation in peripheral tissue; however, its role in the central nervous system (CNS) remains unclear. This study aimed to clarify whether Wip1 can inhibit CNS inflammation by regulating microglia/macrophage functions after ischaemic injury.MethodsA model of middle cerebral artery occlusion and reperfusion was established in mice. CNS inflammation was simulated by lipopolysaccharide treatment of primary microglia. Laser speckle imaging was used to monitor regional cerebral blood flow. Behavioural outcomes were assessed with a TreadScan gait analysis system. TTC staining was used to evaluate the infarct volume, and western blotting and immunofluorescence staining were applied to detect the phenotypical transformation of microglia. ELISA was performed to detect the levels of inflammatory factors.ResultsWip1 expression was increased after ischaemia/reperfusion. Wip1-knockout (KO) mice displayed more severe brain injury than wild-type mice, as indicated by aggravated motor dysfunction, greater brain infarct volumes and higher expression of inflammatory cytokines (interleukin-6 and tumour necrosis factor alpha) in the brain. We also found that Wip1 depletion increased microglial/macrophage activation in both in vitro and in vivo models, which all showed activation of microglia/macrophages. Lentivirus-Ppm1d reversed the injury induced by Wip1-KO.ConclusionsOur results suggest that Wip1 may inhibit neuroinflammation by inhibiting microglial/macrophage activation after brain ischaemia/reperfusion injury.

Targeting p53 for neuroinflammation: New therapeutic strategies in ischemic stroke

“…Wip1 can inhibit p53 phosphorylation and negatively regulate the activity of p53 and NF‐κB, thus alleviating DNA damage, autophagy, and inflammation (Wang et al, 2020). F. Yan et al (2021) found that Wip1 −/− mice showed more severe motor dysfunction, larger cerebral infarction volume, and higher levels of inflammatory factors (IL‐6 and TNF‐α) than wild‐type mice. Wip1 knockout increased the proinflammatory activation of microglia/macrophages and the phosphorylation of p53, thus aggravating the inflammatory response, suggesting that Wip1 might inhibit neuroinflammation by inhibiting p53 activation in microglia/macrophages after cerebral ischemia/reperfusion injury (Figure 2c).…”

Mitogen Activated Protein Kinase (MAPK) Activation, p53, and Autophagy Inhibition Characterize the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike Protein Induced Neurotoxicity

“…In conditions of brain injury, the expression of Wip1 in the nervous tissue prevents inflammation by inhibiting microglial and macrophage accumulation [ 108 ]. In murine and human macrophages, the SARS-CoV-2 spike protein, and specifically the S1 subunit of the trimer, activates NF-κB and c-Jun N-terminal kinase (JNK) pathways specifically via TLR4 activation [ 14 ].…”

Natural Compounds for SIRT1-Mediated Oxidative Stress and Neuroinflammation in Stroke: A Potential Therapeutic Target in the Future

“…Microglia are resident macrophages in the central nervous system. When they detect ischemia, they initiate a response immediately [ 94 , 95 , 96 ]. Microglial activation in the peri-infarct zone within 30 minutes to 1 hour after MCAO is accompanied by the appearance of CD11b, CD45, and Iba1 [ 97 , 98 ].…”