SENP6 induces microglial polarization and neuroinflammation through de-SUMOylation of Annexin-A1 after cerebral ischaemia–reperfusion injury

Abstract

Background Previous data have reported that Sentrin/SUMO-specific protease 6 (SENP6) is involved in ischaemic brain injury and induces neuronal apoptosis after cerebral ischaemia, but the role of SENP6 in microglia-induced neuroinflammation and its underlying mechanism remain poorly understood. This research systematically explored the function and potential mechanism of SENP6 in microglia-induced neuroinflammation after ischaemic stroke. Results We first identified an increased protein level of SENP6 in microglia after cerebral ischaemia. Then, we demonstrated that SENP6 promoted detrimental microglial phenotype polarization. Specifically, SENP6-mediated de-SUMOylation of ANXA1 targeted the IκB kinase (IKK) complex and selectively inhibited the autophagic degradation of IKKα in an NBR1-dependent manner, activating the NF-κB pathway and enhancing proinflammatory cytokine expression. In addition, downregulation of SENP6 in microglia effectively reduced cocultured neuronal damage induced by ischaemic stroke. More importantly, we employed an AAV-based technique to specifically knockdown SENP6 in microglia/macrophages, and in vivo experiments showed that SENP6 inhibition in microglia/macrophages notably lessened brain ischaemic infarct size, decreased neurological deficit scores, and ameliorated motor and cognitive function in mice subjected to cerebral ischaemia surgery. Conclusion We demonstrated a previously unidentified mechanism by which SENP6-mediated ANXA1 de-SUMOylation regulates microglial polarization and our results strongly indicated that in microglia, inhibition of SENP6 may be a crucial beneficial therapeutic strategy for ischaemic stroke. Graphical Abstract

A cell‐penetrating peptide exerts therapeutic effects against ischemic stroke by mediating the lysosomal degradation of sirtuin 5

“…Membrane trafficking and release of ANXA1 have anti‐inflammatory effects and alleviate neuronal damage caused by OGD/R 15,27 . Nevertheless, evidences also suggest that the nuclear transport of ANXA1 may promote proinflammatory factor expression in microglia after ischemia 45,48 . The findings of this study suggest that Tat‐SIRT5‐CTM regulates the subcellular distribution of ANXA1.…”

The role of SUMOylation in the neurovascular dysfunction after acquired brain injury

“…Annexin-A1 SUMOylation regulates microglial polarization after cerebral ischemia by modulating the IκB kinase stability via selective autophagy and significantly improves the neurological functions in a mouse model of ischemic ( Li et al, 2021 ). The expression of SENP6 in microglia increases significantly after cerebral ischemia, and after downregulation of SENP6 in microglia, positive results were obtained, whereby not only did the area of cerebral infarction reduce significantly but the motor and cognitive functions of mice with cerebral ischemia also improved substantially ( Mao et al, 2022 ). However, opposite results have also been reported.…”

“…1.1 Neurovascular dysfunction after acquired brain injury 1.1.1 Pathology of ABI Acquired Brain Injury (ABI) typically is classified into the two following types: traumatic brain injury (TBI) and non-TBI (non-TBI) (Bruns and Hauser, 2003), with the former having the highest incidence among neurological diseases (Maas et al, 2022). The causes of TBI include traffic accidents, violence, and other accidents 1 .…”

Gene therapy of adeno‐associated virus (AAV) vectors in preclinical models of ischemic stroke

“…102,103 After injection, most transgenes are expressed around the injection site, with not only main neuron tropism but also transduction of astrocytes or microglia. 50,52,71,79 AAV2 is currently considered the most extensively studied serotype, but AAV9 appears to be used most frequently in ischemic stroke. 59,62,70,73,80,81 When delivered intravenously, AAV9 can traverse the BBB to target newborn neurons and adult glial cells, 29 and drive axonal transport.…”

“…The AAV1, 2, 5, 6, 7, 8, 9, rh 10, retro, and PHP.B are used more in preclinical stroke research 102,103 . After injection, most transgenes are expressed around the injection site, with not only main neuron tropism but also transduction of astrocytes or microglia 50,52,71,79 . AAV2 is currently considered the most extensively studied serotype, but AAV9 appears to be used most frequently in ischemic stroke 59,62,70,73,80,81 .…”