| First Author | Pan Y | Year | 2021 |
| Journal | Front Cell Neurosci | Volume | 15 |
| Pages | 664312 | PubMed ID | 34262436 |
| Mgi Jnum | J:322580 | Mgi Id | MGI:6729462 |
| Doi | 10.3389/fncel.2021.664312 | Citation | Pan Y, et al. (2021) Inhibition of Perforin-Mediated Neurotoxicity Attenuates Neurological Deficits After Ischemic Stroke. Front Cell Neurosci 15:664312 |
| abstractText | Perforin-mediated cytotoxicity plays a crucial role in microbial defense, tumor surveillance, and primary autoimmune disorders. However, the contribution of the cytolytic protein perforin to ischemia-induced secondary tissue damage in the brain has not been fully investigated. Here, we examined the kinetics and subpopulations of perforin-positive cells and then evaluated the direct effects of perforin-mediated cytotoxicity on outcomes after ischemic stroke. Using flow cytometry, we showed that perforin(+)CD45(+) immune cells could be detected at 12 h and that the percentage of these cells increased largely until on day 3 and then significantly declined on day 7. Surprisingly, the percentage of Perforin(+)CD45(+) cells also unexpectedly increased from day 7 to day 14 after ischemic stroke in Perforin1-EGFP transgenic mice. Our results suggested that Perforin(+)CD45(+) cells play vital roles in the ischemic brain at early and late stages and further suggested that Perforin(+)CD45(+) cells are a heterogeneous population. Surprisingly, in addition to CD8(+) T cells, NK cells, and NKT cells, central nervous system (CNS)-resident immune microglia, which are first triggered and activated within minutes after ischemic stroke in mice, also secreted perforin during ischemic brain injury. In our study, the percentage of perforin(+) microglia increased from 12 h after ischemic stroke, increased largely until on day 3 after ischemic stroke, and then moderately declined from days 3 to 7. Intriguingly, the percentage of perforin(+) microglia also dramatically increased from days 7 to 14 after ischemic stroke. Furthermore, compared with wild-type littermates, Perforin 1(-/-) mice exhibited significant increases in the cerebral infarct volume, neurological deficits, and neurogenesis and inhibition of neurotoxic astrogliosis. Interestingly, the number of CD45(+)CD3(+) T cells was significantly decreased in Perforin 1(-/-) mice compared with their wild-type littermates, especially the number of gammadelta T cells. In addition, Perforin 1(-/-) mice had lower levels of IL-17 than their wild-type littermates. Our results identified a critical function of perforin-mediated neurotoxicity in the ischemic brain, suggesting that targeting perforin-mediated neurotoxicity in brain-resident microglia and invading perforin(+)CD45(+) immune cells may be a potential strategy for the treatment of ischemic stroke. |
