Suppression of oxidative neuronal damage after transient middle cerebral artery occlusion in mice lacking interleukin-1 (original) (raw)
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Journal of Cerebral Blood Flow & Metabolism, 2005
Excessive inflammation has been implicated in the progressive neurodegeneration that occurs in multiple neurological diseases, including cerebral ischemia, and elevated levels of the proinflammatory cytokine interleukin-1 (IL-1) have been shown to exacerbate brain damage, whereas diminishing IL-1 levels limits the extent of injury. However, to date there is no consensus regarding which receptor(s) mediates the detrimental effects of IL-1. Because we have previously demonstrated that signaling through the IL-1 type 1 receptor (IL-1R1) is necessary for microglial activation and because results from other studies have implicated microglia as effectors of neurodegeneration, we hypothesized that inactivating the IL-1R1 would decrease the extent of damage caused by a hypoxic-ischemic (H/I) insult. It is shown that a mild insult initiates progressive neurodegeneration that leads to cystic infarcts, which can be prevented by inactivating the IL-1R1. The IL-1R1 null mice also show preserved sensorimotor function at 1 month's recovery. The mild insult induces multiple proinflammatory cytokines and activates microglia, and these responses are dramatically curtailed in mice lacking the IL-1R1. Importantly, the neuroinflammation precedes the progressive enlargement of the infarct, suggesting that the inflammation is causal rather than a consequence of the brain damage. These findings show that abrogating the inflammation consequent to a mild H/I insult will prevent brain damage and preserve neurological function. Additionally, these data incriminate the IL-1R1 as a master proinflammatory cytokine receptor.
Role of IL1a and IL1b in Ischemic Brain Damage
The cytokine interleukin-1 (IL-1) has been strongly implicated in the pathogenesis of ischemic brain damage. Evidence to date suggests that the major form of IL-1 contributing to ischemic injury is IL-1b rather than IL-1a, but this has not been tested directly. The objective of the present study was to compare the effects of transient cerebral ischemia (30 min middle cerebral artery occlusion (MCAO)) on neuronal injury in wild-type (WT) mice and in IL-1a, IL-1b, or both IL-1a and IL-1b knock-out (KO) mice. Mice lacking both forms of IL-1 exhibited dramatically re- duced ischemic infarct volumes compared with wild type (total volume, 70%; cortex, 87% reduction). Ischemic damage com- pared with WT mice was not significantly altered in mice lacking either IL-1a or IL-1b alone. IL-1b mRNA, but not IL-1a or the IL-1 type 1 receptor, was strongly induced by MCAO in WT and IL-1a KO mice. Administration (intracerebroventricularly) of recombinant IL-1 receptor antagonist significantly reduce...
The Journal of Neuroscience, 2002
The cytokine interleukin-1 (IL-1) contributes to ischemic, excitotoxic, and traumatic brain injury. IL-1 actions depend on interaction with a single receptor (IL-1RI), which associates with an accessory protein (IL-1RAcP), and is blocked by IL-1 receptor antagonist (IL-1ra). Here we show that in normal mice [wild-type (WT)], intracerebroventricular injection of IL-1ra markedly reduces (Ϫ50%; p Ͻ 0.01) ischemic brain damage caused by reversible occlusion of the middle cerebral artery, whereas injection of IL-1 exacerbates damage (ϩ45%; p Ͻ 0.05). Mice lacking IL-1RI [IL-1RI knockout (KO)] exhibited ischemic brain damage that is almost identical to that of the WT (infarct volume 43.7 Ϯ 6.1 and 46.2 Ϯ 6.2 mm 3 , respectively), but failed to respond to injection of IL-1ra. However, injection of IL-1 (intracerebroventricularly) exacerbated ischemic brain damage in IL-1RI KO (ϩ61%; p Ͻ 0.001) and in WT mice (ϩ45%). This effect of IL-1 was abolished by heat denaturation in all animals, and was reversed by IL-1ra in WT, but not IL-1RI KO mice. In contrast, IL-1RI KO mice were completely resistant to effects of IL-1 on food intake or body weight. IL-1RAcP mRNA was increased by stroke in WT, but reduced in IL-1RI KO mice compared with sham-operated mice. Type II IL-1 receptor mRNA was significantly increased 4 hr after ischemia in WT and IL-1RI KO (ϩ20%) animals. These data show that IL-1 can exacerbate ischemic brain damage independently of IL-1RI and suggest the existence of additional signaling receptor or receptors for IL-1 in the brain.
Brain, Behavior, and Immunity, 2018
The cytokine interleukin-1 (IL-1) is a key contributor to neuroinflammation and brain injury, yet mechanisms by which IL-1 triggers neuronal injury remain unknown. Here we induced conditional deletion of IL-1R1 in brain endothelial cells, neurons and blood cells to assess site-specific IL-1 actions in a model of cerebral ischaemia in mice. Tamoxifen treatment of IL-1R1 floxed (fl/fl) mice crossed with mice expressing tamoxifen-inducible Cre-recombinase under the Slco1c1 promoter resulted in brain endothelium-specific deletion of IL-1R1 and a significant decrease in infarct size (29%), blood-brain barrier (BBB) breakdown (53%) and neurological deficit (40%) compared to vehicle-treated or control (IL-1R1 fl/fl) mice. Absence of brain endothelial IL-1 signalling improved cerebral blood flow, followed by reduced neutrophil infiltration and vascular activation 24 h after brain injury. Conditional IL-1R1 deletion in neurons using tamoxifen inducible nestin-Cre mice resulted in reduced neuronal injury (25%) and altered microglia-neuron interactions, without affecting cerebral perfusion or vascular activation. Deletion of IL-1R1 specifically in cholinergic neurons reduced infarct size, brain oedema and improved functional outcome. Ubiquitous deletion of IL-1R1 had no effect on brain injury, suggesting beneficial compensatory mechanisms on other cells against the detrimental effects of IL-1 on endothelial cells and neurons. We also show that IL-1R1 signalling deletion in platelets or myeloid cells does not contribute to brain injury after experimental stroke. Thus, brain endothelial and neuronal (cholinergic) IL-1R1 mediate detrimental actions of IL-1 in the brain in ischaemic stroke. Cell-specific targeting of IL-1R1 in the brain could therefore have therapeutic benefits in stroke and other cerebrovascular diseases.
Brain Research, 2010
The proinflammatory cytokine interleukin(IL)-1β plays a crucial role in ischemic pathophysiology, since pharmacologic inhibition of its biological effects provides neuroprotection after stroke. However, there is evidence suggesting that under certain circumstances the cytokine may also exert beneficial functions on brain injury. We have investigated the regional and cellular expression of IL-1β after ischemia-reperfusion injury in the brain of rat, and correlated cytokine expression with the activation/recruitment of glial cells in the damaged tissue. By using a double immunofluorescence histochemical approach, we observed an increased cytokine immunoreactivity in the ischemic core, as early as 1 h after middle cerebral artery occlusion, in few activated OX-42-positive microglial cells and in perivascular GFAP-positive astrocytes, suggesting that the cytokine may participate in the early response of the neurovascular unit to reduced blood supply. After 2 h ischemia, followed by 2 h reperfusion, cytokine staining was evident in the astrocytes of the penumbra and in activated microglial cells of the ischemic core. Microglial activation increases with the progression of damage and, after 22 h reperfusion, OX-42immunopositive cells were strongly labelled for IL-1β in the core and, even more intensely, in the penumbra. At this later stage, GFAP-positive cells, appearing hypertrophic and distributed in a ring-like pattern around the ischemic core, do no longer express IL-1β. Thus, a specific cellular and regional pattern of IL-1β expression characterises the progression of ischemia-reperfusion injury. Depending on the stage and intensity of the insult, the different cellular origin of the cytokine may suggest a distinct role of this neuroinflammatory mediator in ischemic pathophysiology.
Increased Expression of Interleukin-1.BETA. in Mouse Hippocampus after Global Cerebral Ischemia
ACTA HISTOCHEMICA ET CYTOCHEMICA, 2001
We examined the in vivo expression of IL-1b and its transcript after cerebral ischemia produced in mice cardiac arrest model. The IL-1b mRNA in the hippocampal region reached a detectable level at 1 hr after ischemia and had a peak at 3 hr after ischemia recirculation. But it was markedly decreased at 1 day and reached the control levels at 4 day after ischemia recirculation. The IL-1b-like immunoreactivity was observed at 1, 2, 4 day after ischemia recirculation and its immunoreactivity was detected at 2 day. The IL-1b-like immunoreactivity was observed in both microglia and astrocytes after bran ischemia by double immunostaining. These results provide the direct evidence for the localization and induction of IL-1b expression in vivo in mice after ischemia. It is suggested that IL-1b, produced in both astrocytes and microglia cells after ischemia, directly affect on neurons as well as glial cells to induce delayed neuronal cell death.
The Journal of Neuroscience, 1999
Nitric oxide (NO) is a new intercellular messenger that occurs naturally in the brain without causing overt toxicity. Yet, NO has been implicated as a mediator of cell death in cell death. One explanation is that ischemia causes overproduction of NO, allowing it to react with superoxide to form the potent oxidant peroxynitrite. To address this question, we used immunohistochemistry for citrulline, a marker for NO synthase activity, and 3-nitrotyrosine, a marker for peroxynitrite formation, in mice subjected to reversible middle cerebral artery occlusion. We show that ischemia triggers a marked augmentation in citrulline immunoreactivity but more so in the peri-infarct than the infarcted tissue. This increase is attributable to the activation of a large population (∼80%) of the neuronal isoform of NO synthase (nNOS) that is catalytically inactive during basal conditions, indicating a tight regulation of physiological NO production in the brain. In contrast, 3-nitrotyrosine immunoreac...
Stroke, 2005
Background and Purpose-Interleukin-1 (IL-1) is a proinflammatory cytokine implicated in multiple neurodegenerative diseases, including stroke. However, to date, there is no consensus regarding which receptor(s) mediates the detrimental effects of IL-1. We hypothesized that abrogating IL-1 type 1 receptor (IL-1R1) signaling would reduce edema, chemokine expression, and leukocyte infiltration; lower levels of iNOS; and, consequently, decrease free radical damage after mild hypoxia/ischemia (H/I), thus preserving brain cells. Methods-IL-1R1 null mice and wild-type mice were subjected to a mild H/I insult. MRI was used to measure the area affected at 30 minutes and 48 hours after H/I. An RNAse protection assay was used to evaluate changes in chemokine mRNA expression. RT-PCR was used to assess inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase mRNA levels. Immunohistochemistry was used to assess leukocyte infiltration. Western blots were used to assess iNOS and glutamate aspartate transporter protein levels. Results-IL-1R1 null mice had reduced cytotoxic and vasogenic edema. The volume of hyperintense signal on T 2 -weighted images was reduced on average by 90% at 48 hours after H/I. The induction of multiple chemokine mRNAs was significantly reduced in IL-1R1 null mice compared with wild-type mice at 18 and 72 hours after H/I, which correlated with fewer infiltrating CD3ϩ leukocytes. Levels of iNOS protein and mRNA (but not glutamate aspartate transporter) were significantly reduced in the IL-1R1 mouse brain. Conclusions-These findings indicate that abrogating IL-1R1 signaling could protect brain cells subsequent to a mild stroke by reducing edema and immune cell recruitment, as well as by limiting iNOS-mediated free radical damage. (Stroke. 2005;36:2226-2231.)
Journal of Neuroinflammation, 2011
Background Cerebral ischemia is a devastating condition in which the outcome is heavily influenced by inflammatory processes, which can augment primary injury caused by reduced blood supply. The cytokines interleukin-1α (IL-1α) and IL-1β are key contributors to ischemic brain injury. However, there is very little evidence that IL-1 expression occurs at the protein level early enough (within hours) to influence brain damage after stroke. In order to determine this we investigated the temporal and spatial profiles of IL-1α and IL-1β expression after cerebral ischemia. Findings We report here that in mice, as early as 4 h after reperfusion following ischemia induced by occlusion of the middle cerebral artery, IL-1α, but not IL-1β, is expressed by microglia-like cells in the ischemic hemisphere, which parallels an upregulation of IL-1α mRNA. 24 h after ischemia IL-1α expression is closely associated with areas of focal blood brain barrier breakdown and neuronal death, mostly near the pe...
Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain
Nature Medicine, 2012
Stroke is one of the major causes of death and disability worldwide. The only globally approved treatment for ischemic stroke is tissue plasminogen activator, a time-dependent therapy that must be given within 4.5 h of stroke onset. Consequently, there is an unmet need for therapy that could be commenced beyond this time window and that would be aimed at brain tissue protection rather than clot dissolution 1-3. Recent evidence suggests that various elements of the immune system are intimately involved in all stages of the ischemic cascade, from the acute intravascular events to the parenchymal processes leading to brain damage and tissue repair, which determine the fate of patients after stroke 4-6. In mouse models, immune cells such as T cells and macrophages and their cytokines have been shown to have a pivotal role in the immunomodulation of post-ischemic inflammation 7-10. We have reported that interleukin-23 (IL-23) produced from infiltrating macrophages induces IL-17-producing T cells. IL-17 is mainly produced from γδT cells and promotes delayed (day 3-4) ischemic brain damage 11,12. Despite intensive study of post-ischemic inflammation, the molecular mechanisms that activate infiltrating macrophages remain unclear. TLRs are pivotal in triggering the inflammation of sterile organs 13,14. HMGB1, heat shock proteins (HSPs), β-amyloid (Aβ) and others are well known as endogenous TLR ligands; that is, they are damage-associated molecular pattern molecules (DAMPs) 15-19. Although HMGB1 is implicated in ischemic brain injury, it remains to be clarified whether HMGB1 is the major DAMP involved in the activation of infiltrating immune cells or whether other local DAMPs have roles in this process 20-23. In this study, we identified Prx family proteins in brain lysate as strong inducers of inflammatory cytokines. The extracellular release of Prx proteins occurred 12 h after stroke onset, which coincided with the timing of macrophage infiltration and stimulated infiltrating macrophages via TLR2 and TLR4. Neutralization of Prx proteins rather than HMGB1 by specific antibodies suppressed inflammatory cytokine expression in the ischemic brain. Thus, extracellular Prx could be a previously unknown DAMP that triggers post-ischemic inflammation and an ideal therapeutic target for ischemic brain injury. RESULTS Peroxiredoxins are potent IL-23 inducers in brain lysate To determine whether there are DAMPs that induce IL-23 in the brain, we cultured bone marrow-derived dendritic cells (BMDCs) with a brain homogenate supernatant (brain lysate) from mice. mRNA encoding IL-23 p19 and other cytokine mRNAs were rapidly induced in BMDCs by incubation with the brain lysate (Fig. 1a and