The Progression and Topographic Distribution of Interleukin-1β Expression after Permanent Middle Cerebral Artery Occlusion in the Rat (original) (raw)
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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.
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...
Stroke, 2000
Background and Purpose —The purpose of this study was (1) to examine the contribution of microglia and macrophages with their interleukin-1β production and (2) to assess the vulnerability and response of oligodendrocytes in cerebral infarction. Methods —Male Wistar rats were subjected to permanent occlusion of the left middle cerebral artery. Expansion of ischemic infarction and response of oligodendrocytes were investigated together with accumulation of inflammatory cells, production of interleukin-1β, and disruption of the blood-brain barrier. Apoptotic cell death was inferred from fragmented DNA and the expression of proapoptotic Bax protein. Results —During expansion of infarction, amoeboid microglia and extravasation of serum albumin were observed not only in the infarcted area but also in the adjacent surviving area, whereas macrophages accumulated along the boundary and granulocytes migrated into the center of the infarction. Both amoeboid microglia and macrophages produced i...
2000
Background and Purpose-The purpose of this study was (1) to examine the contribution of microglia and macrophages with their interleukin-1 production and (2) to assess the vulnerability and response of oligodendrocytes in cerebral infarction. Methods-Male Wistar rats were subjected to permanent occlusion of the left middle cerebral artery. Expansion of ischemic infarction and response of oligodendrocytes were investigated together with accumulation of inflammatory cells, production of interleukin-1, and disruption of the blood-brain barrier. Apoptotic cell death was inferred from fragmented DNA and the expression of proapoptotic Bax protein. Results-During expansion of infarction, amoeboid microglia and extravasation of serum albumin were observed not only in the infarcted area but also in the adjacent surviving area, whereas macrophages accumulated along the boundary and granulocytes migrated into the center of the infarction. Both amoeboid microglia and macrophages produced interleukin-1, an inflammatory cytokine, during an early ischemic period. Furthermore, macrophages within the infarcted tissue expressed Bax protein and subsequently showed fragmented nuclear DNA. Oligodendrocytes were detected in the infarcted area even after 24 hours following middle cerebral artery occlusion, but they subsequently developed fragmented DNA. A week after onset of ischemia, oligodendrocytes were found to be accumulated in the intact area bordered with the infarct together with reactive astrocytes. Conclusions--Our results suggest the importance of amoeboid microglia, macrophages, and their interleukin-1 production in gradual expansion of cerebral infarction. Resident oligodendrocytes may be resistant to ischemic insults, and oligodendrocytes accumulated at the border of the infarction may participate in tissue repair after cerebral infarction.
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.
Induction of interleukin-1β mRNA after focal cerebral ischaemia in the rat
Molecular Brain Research, 1994
The expression of interleukin-1/3 (IL-1/3) mRNA in the brain in response to cerebral ischaemia in rats was examined using in situ hybridization histochemistry. Focal cerebral ischaemia was induced in spontaneously hypertensive rats by permanent occlusion of the left middle cerebral artery (MCAO). Whereas no IL-1/3 mRNA could be detected in non-operated and sham-operated rats, middle cerebral artery occlusion induced the expression of IL-1/3 mRNA within 15 min in the ischaemic brain regions prone to become necrotic after 1-2 days. The message appeared as spot-like signals, reached a peak after 3 h and then declined to undetectable levels within 4 days. Additionally, a pronounced but brief induction of IL-1/3 mRNA could be detected 1 h after MCAO in the meninges near the watershed zone. The results demonstrate that the inflammatory cytokine IL-1/3 is induced in a time-dependent way after brain ischaemia.
Journal of Cerebral Blood Flow & Metabolism, 2000
The proinflammatory cytokine tumor necrosis factor (TNF) is known to be expressed in brain ischemia; however, its cellular and temporal appearance is not fully settled. In this study, nonradioactive in situ hybridization for murine TNF mRNA was performed on brain sections from adult C57×129 mice at 6 hours, 12 hours, 24 hours, 2 days, 5 days, or 10 days (six to eight mice per group) after induction of permanent focal cerebral ischemia. Cortical infarct volumes were estimated, and TNF mRNA-expressing cells were counted within the infarct and infarct border using Cast-Grid analysis. At 12 hours, a peak of 19.2 ± 5.1 TNF mRNA-expressing cells/mm2 was counted, contrasting two to three times lower values at 6 and 24 hours (6.4 ± 4.6 and 9.2 ± 3.4 cells/mm2, respectively) and <2 cells/ mm2 at 48 hours and later stages. The TNF mRNA-expressing cells were distributed along the entire rostrocaudal axis of the cortical infarcts and occasionally within the caudate putamen. At all time point...
Background and Objective: Clinical and experimental observations emphasize the role of inflammation as a direct risk factor for stroke. To better characterize the inflammation, we have conducted a detailed histological analysis of the inflammatory cell population after transient middle cerebral artery occlusion in a rat model. Methods: Fifteen adult Wistar male rats were divided randomly into test (n=10) and sham (n=5) groups. In the ischemic group, transient focal cerebral ischemia was induced with an intraluminal filament technique. Histologic lesions of the ischemic core and the surrounding penumbra zone were evaluated, based on a complex algorithm. Representative morphological changes in the core and the penumbra zone were compared. Immunohistochemistry was performed for leukocytes markers (CD15, CD68, CD3), leukocyte-released effectors (MMP-9 and COX-2), and FXIII (possibly involved in microglia and macrophage activation) Results: Neuronal vacuolation and degeneration were sign...
Acta Neuropathologica, 2004
Interleukin-1 receptor antagonist (IL-1ra) has been shown previously to have neuroprotective effects in animal models of stroke. The effects of chronic overexpression of human soluble IL-1ra (hsIL-1ra) were studied in a mouse model of permanent focal cerebral ischemia. A transgenic mouse strain (Tg hsIL-1ra +/-) has been developed using the promoter for glial fibrillary acidic protein (GFAP) to limit the overexpression to the CNS. Analysis of the neurological scores, infarct volume and edema formation revealed no differences between Tg hsIL-1ra +/and wild-type (WT) mice. The cerebral ischemia resulted in pronounced astrocyte proliferation and microglial activation, as well as induction of inflammatory markers in both Tg hsIL-1ra +/and WT mice, with no major differences between the two genotypes. Interestingly, hsIL-1ra expression in astrocytes was reduced in infarcted areas as compared to non-ischemic regions and sham-operated controls. In conclusion, transgenic overex-pression of hsIL1-ra was not neuroprotective in this cerebral ischemia model, possibly due to insufficient levels for protection against the extensive lesion, or an up-regulation of compensatory inflammatory signals due to the lifetime blockade of IL-1 receptors.
Neuroscience Research, 2003
Interleukin-1 (IL-1) contributes to ischemic neurodegeneration. However, the mechanisms regulating action of IL-1 are still poorly understood. In order to clear this central issue, mice that were gene deficient in IL-1a and b (IL-1 KO) and wild-type mice were subjected to 1-h transient middle cerebral artery occlusion (tMCAO). Expression levels of IL-1b and IL-1 receptor I (IL-1RI) were then examined. Generation of peroxynitrite and the expression of mRNAs for nitric oxide synthase (NOS) subtypes were also determined. Immunostaining for IL-1b was increased from 6 h and peaked at 24 h after tMCAO in the microglia and macrophage. The immunoreactivities of IL-1RI were increased progressively in the microvasculature and neuron-like cells of the ipsilateral hemisphere. Infarct volumes were significantly lower in IL-1 KO mice compared with wild-type mice 48 h after tMCAO (P B/0.01). The immunoreactivities of 3-nitro-L-tyrosine were determined in the neurons and microvasculature 24 h after tMCAO and were significantly decreased in the IL-1 KO mice compared to wild-type mice. In addition, expression levels of NOS mRNA in IL-1 KO mice were lower than that measured in wild-type mice. These results indicate that IL-1 is up-regulated and may play a role in neurodegeneration by peroxynitrite production during ischemia. #