Interleukin-1 Mediates Ischemic Brain Injury via Induction of IL-17A in γδ T Cells and CXCL1 in Astrocytes

NeuroMolecular Medicine - Tập 24 - Trang 437-451 - 2022
Ines Sophie Schädlich1, Jonas Heinrich Vienhues1,2, Alina Jander1, Marius Piepke1, Tim Magnus1, Kate Lykke Lambertsen2,3,4, Bettina Hjelm Clausen2,3, Mathias Gelderblom1
1Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg-Eppendorf, Germany
2Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
3BRIDGE - Brain Research - Inter Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense, Denmark
4Deparment of Neurology, Odense University Hospital, Odense, Denmark

Tóm tắt

As a prototypical proinflammatory cytokine, interleukin-1 (IL-1) exacerbates the early post-stroke inflammation, whereas its neutralization is protective. To further investigate the underlying cell-type-specific IL-1 effects, we subjected IL-1 (α/β) knockout (Il1−/−) and wildtype (WT) littermate mice to permanent middle cerebral artery occlusion (pMCAO) and assessed immune cell infiltration and cytokine production in the ischemic hemisphere by flow cytometry 24 h and 72 h after stroke. Il1−/− mice showed smaller infarcts and reduced neutrophil infiltration into the ischemic brain. We identified γδ T cells and astrocytes as target cells of IL-1 signaling-mediated neutrophil recruitment. First, IL-1-induced IL-17A production in γδ T cells in vivo, and IL-17A enhanced the expression of the main neutrophil attracting chemokine CXCL1 by astrocytes in the presence of tumor necrosis factor (TNF) in vitro. Second, IL-1 itself was a potent activator of astrocytic CXCL1 production in vitro. By employing a novel FACS sorting strategy for the acute isolation of astrocytes from ischemic brains, we confirmed that IL-1 is pivotal for Cxcl1 upregulation in astrocytes in vivo. Our results underscore the pleiotropic effects of IL-1 on immune and non-immune cells within the CNS to mount and amplify the post-stroke inflammatory response.

Tài liệu tham khảo

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