Neutralization of the IL-17 axis diminishes neutrophil invasion and protects from ischemic stroke

Abstract

The devastating effect of ischemic stroke is attenuated in mice lacking conventional and unconventional T cells, suggesting that inflammation enhances tissue damage in cerebral ischemia. We explored the functional role of ␣␤ and ␥␦ T cells in a murine model of stroke and distinguished 2 different T cell-dependent proinflammatory pathways in ischemiareperfusion injury. IFN-␥ produced by IntroductionIschemic stroke represents a major cause of disability and death in the western world. 1 Although infiltration of inflammatory leukocytes is a well-described feature of human stroke, 2 the perspective that activation of the immune systems is a bystander phenomenon secondary to ischemic tissue damage has changed. Currently, the activation of the immune system is recognized as a major element in all stages of the pathophysiology of stroke, including long lasting regenerative processes. 1,3 Release of danger molecules, local expression of proinflammatory cytokines, the subsequent expression of endothelial adhesion molecules, and breakdown of the blood-brain barrier are among the initial events after arterial occlusion. 3 These events are followed by an amplification of the postischemic inflammation that involves both resident brain cells and infiltrating immune cells. With the use of a mouse model of middle cerebral artery occlusion (MCAO), our group has previously shown a sequentially organized accumulation of immune cells of both the innate and adaptive immune systems in the ischemic brain. 4 The cellular infiltrate is dominated by neutrophils, macrophages, and microglia, but also includes T, natural killer, and dendritic cells.At this early stage, different T-cell subpopulations play important roles even if their absolute abundance in the ischemic brain is low. CD4 ϩ and CD8 ϩ T cells, as well as ␥␦ T cells, promote further tissue damage, 5-8 whereas regulatory T cells and B cells are protective. 9,10 Cytokines involved in the proinflammatory response include IL-1␤, IL-12, and IL-23, as well as interferon ␥ (IFN-␥), IL-17A, and TNF-␣. In contrast IL-4, TGF-␤, and mostly IL-10 are part of protective pathways. 9,11,12 However, the specific integration of each cell type and cytokine in the postischemic inflammatory network still has to be elucidated.In sterile inflammations, including ischemia, IL-17A can be crucial for chemokine induction. 13,14 Importantly, IL-17A can be rapidly released by ␥␦ T cells in response to cytokine activation or engagement of innate receptors, in the absence of TCR activation. 15 Beside IL-17A, IFN-␥ pathways are also implicated in ischemia/reperfusion (I/R) injury. 13,16 In autoimmunity, IFN-␥ production is associated with induction of MHCII expression, production of chemokines, and activation of macrophages. 17 Our analysis of the evolving local and systemic inflammatory responses after stroke has yielded 2 new distinct and crosslinked pathways: First, IFN-␥ produced by ␣␤ T cells induces the expression of TNF-␣ in macrophages. Second, ␥␦ T cells lead to neutrophil infiltration via the IL-1...

PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model

“…Astrocytes also produce and release TNF but they are not sensitive to PI3Kd inhibition in vitro as they do not exhibit PI3Kd immunoreactivity, suggesting different trafficking regulators might control TNF release in these cells. The lack of PI3Kd detection in astrocytes in vitro indicates that the observed decrease in astrocytic TNF in vivo under I/R may result from attenuated proinflammatory feedback cascades 5,43,44 stemming from reduced microglial TNF secretion. Our study is in good agreement with other studies pointing to a key role of microglial TNF in early-phase inflammation in the CNS 13 .…”

Antigen Presentation After Stroke

“…T cells are known to have detrimental effects in stroke by promoting leukocyte adherence to the brain vasculature [12] and triggering thromboinflammation [13] in animals. The presence of T cells and γδ lymphocytes was also reported in mouse and human brain tissue 24 h after stroke [14]. These effects are rapid and lack antigen specificity.…”

Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature

“…For example, Yilmaz et al were able to show that reconstitution of Rag1 Ϫ/Ϫ mice with CD4 ϩ Th cells or CD8 ϩ cytotoxic T cells reversed the protection from stroke in these animals, 6 which is consistent with our results after adoptive transfer of CD4 ϩ CD25 Ϫ non-Tregs. Moreover, other studies recently stressed the stroke-promoting function of so-called ␥⌬ T cells, a specialized subpopulation of T cells placed at the intersection between the innate and the adaptive immune system, at least during later stages of infarct development, 30,53 whereas these cells do not appear to play a major pathophysiologic role early after tMCAO. 8 We recently showed that natural Tregs bear an intrinsic propensity for migration, thus increasing the probability of a Treg-endothelial cell interaction compared with non-Tregs.…”