Editors' ChoiceStroke

Neutralizing Neutrophil Invasion

See allHide authors and affiliations

Science Translational Medicine  26 Sep 2012:
Vol. 4, Issue 153, pp. 153ec174
DOI: 10.1126/scitranslmed.3004989

Stroke caused by obstruction of blood flow to a part of the brain (ischemic stroke) can be deadly. However, not all of the consequences of stroke stem directly from the interruption of blood flow; some of them are caused by “friendly fire” from the body’s own immune system. In particular, the invasion of neutrophils into the injured area is known to cause tissue damage, but the exact role that each cell type and cytokine plays in the postinflammatory network is currently unknown. Now, a new study by Gelderblom et al. provides further insights into this post-stroke inflammatory cytokine and immune cell network.

Using a mouse model of stroke, the authors found that conventional (αβ) T cells and unconventional (γδ) T cells secreting interferon γ (IFN-γ) and interleukin 17A (IL-17A), respectively, were present in the injured tissue after a period of ischemia followed by reperfusion. IFN-γ then induced macrophages infiltrating the stroke site to produce tumor necrosis factor–α (TNF-α). TNF-α together with IL-17A attracted tissue-damaging neutrophils to the injured area through the induction of CXCL-1 in astrocytes. IL-17A further contributed to tissue damage independent of the neutrophil effects by up-regulating other inflammatory mediators, such as matrix metalloproteinase 3, which led to a breakdown of the blood-brain barrier. Additionally, in vivo studies in mice demonstrated that inhibiting IL-17A binding to its receptor by antibodies to IL-17A resulted in a significant reduction in the size of the injured tissue and improvement in clinical outcome. Post mortem analysis of tissues from human stroke patients showed similar immune cells and inflammatory cytokines in the injured sites. This observation suggests that the T cell/IL-17/neutrophil axis might be involved in the pathogenesis of ischemia/reperfusion injury after stroke in humans as well, providing a rationale for testing the efficacy of antibodies to IL-17A in patients with stroke.

Gelderblom and colleagues elucidated the role that immune cells and their cytokines play in the post–ischemic stroke inflammatory network and provided preliminary evidence that neutralizing IL-17A antibodies may reduce the severity of stroke. Additional studies in larger animal models and humans are necessary to further explore the feasibility and efficacy of this therapeutic approach, but this new discovery does offer hope of reducing neutrophil invasion in stroke victims and decreasing the rates of the resulting disability and death.

M. Gelderblom et al., Neutralization of the IL-17 axis diminishes neutrophil invasion and protects from ischemic stroke. Blood, published online 13 September 2012 (10.1182/blood-2012-02-412726 ) [Abstract]

Stay Connected to Science Translational Medicine

Navigate This Article