- Original Articles
- Open Access
Expression of TNF and TNF Receptors (p55 and p75) in the Rat Brain after Focal Cerebral Ischemia
© Picower Institute Press 1997
- Accepted: 24 September 1997
- Published: 1 November 1997
Cerebral ischemia induces a rapid and dramatic up-regulation of tumor necrosis factor (TNF) protein and mRNA, but the cellular sources of TNF in the ischemic brain have not been defined. The diverse activities of TNF are mediated via ligand interaction with two distinct receptors, p55 and p75, which activate separate intracellular signal transduction pathways, leading to distinct biological effects. Since the effects of cerebral ischemia on TNF receptor (TNFR) expression are unknown, we examined the cellular localization and protein expression of TNF and its two receptors in the rat cerebral cortex in response to permanent middle cerebral artery (MCA) occlusion. The results indicate that focal cerebral ischemia up-regulates expression of TNF and both TNFRs within the ischemic cortex. The most abundant type of TNF irrimunoreactivity (ER) was a punctate and filamentous pattern of transected cellular processes; however, cell bodies of neurons, astrocytes, and microglia, as well as infiltrating polymorphonuclear (PMN) leukocytes also showed TNF IR. Brain vasculature displayed TNF IR not only within endothelial cells but also in the perivascular space. MCA occlusion induced significant up-regulation of TNF receptors, with p55 IR appearing within 6 hr, significantly before the appearance of p75 IR at 24 hr after the onset of ischemia. Since p55 has been implicated in transducing cytotoxic signalling of TNF, these results support the proposed injurious role of excessive TNF produced during the acute response to cerebral ischemia.
Tumor necrosis factor (TNF), a pleiotropic cytokine produced during the physiological response to infection, injury, or ischemia, has been implicated in disease pathophysiologies of the central nervous system (CNS) such as cerebral meningitis, cerebral malaria, multiple sclerosis, Alzheimer’s disease, HIV encephalopathy, and cerebral ischemia. A large body of evidence suggests that the relative overproduction of TNF during cerebral ischemia amplifies and extends the severity of cell death during brain ischemia. The expression of TNF protein and mRNA are stimulated during cerebral ischemia, with peak protein expression occurring by 6 hr after the onset of ischemia (1), or shortly thereafter (2). In animal models of head injury, TNF synthesis is also increased, possibly secondarily to the onset of cerebral ischemia (3–6). Cerebral hypoxia-isch-emia increased TNF mRNA in perinatal rat brain (7), and an early and marked increase of TNF in neuronal somata has been observed following surgical injury (5).
As in other biological conditions in which low levels of TNF can be beneficial, but higher levels are injurious (8), excessive intracerebral TNF in the context of cerebral ischemia is damaging. Therapeutic implications are suggested by the attenuation of brain-damaging ischemic sequelae following administration of anti-TNF antibodies or receptor constructs. Repeated intracerebroventricular administration (9), or intracortical injection of anti-TNF antibodies (10) significantly limited the volume of ischemic brain damage. The administration of soluble type 1 TNF receptors (TNFRs) significantly protected against the development of brain infarction in SHR rats (11). Topical application of a dimeric polyethylene glycol-linked TNFR1 also significantly protected against focal cerebral infarction in BALB/c mice (12). Evidence for a protective role of TNF in cerebral ischemia was observed in genetically engineered knock-out mice rendered devoid of TNF receptors, which develop significantly larger cerebral infarctions than wild-type controls (13). Considered together, these results indicate that in response to ischemia, low levels of TNF may be beneficial, but excessive production of the cytokine is deleterious.
TNF can be produced by many cells, including lymphocytes, natural killer cells, endothelial cells, mast cells, smooth muscle cells, etc. (14,15). In the CNS, microglia (16,17), astrocytes (18–20) and choroid plexus ependymal cells (21) have each been shown to produce TNF in vitro. The pleiotropic activities of TNF are mediated via ligand interaction with two distinct TNF receptors termed TNFR1, or p55, and TNFR2, or p75, that are independently expressed on a variety of cells including neurons and glial cells (reviewed in refs. 22–26). Each receptor can be cleaved into a soluble form that is capable of binding and neutralizing TNF. Cell expression of the TNF receptors is closely regulated in response to ischemia and injury, providing an important level of control over the biological activities of TNF. Moreover, the cellular responses to TNF are determined differently by these two receptor populations as they activate separate intracellular signal transduction pathways that modulate distinct cellular responses. For instance, the p55 receptor mediates TNF-induced apoptotic cell death (reviewed in ref. 27), but the function of p75 is more obscure. It has been implicated in cell proliferation and protection against death (28,29), although it is capable of transducing apoptotic signals in certain cell lines (30). Tada et al. (31) recently found that p55 mRNA was weakly expressed in normal brain. Inhibition of p75 by antisense oligonucleotides significantly increased TNF-, hypoxia- and beta amyloid-mediated neuronal cell death (32), suggesting that p75 TNFR may participate in protective responses following insult or injury.
Despite the importance of TNF in the mediation of cerebral ischemia, cellular sources of TNF and the expression of TNF receptors are incompletely characterized. Accordingly, we examined here the expression and cellular localization of TNF and two TNF receptors in the cerebral cortex after permanent MCA occlusion. Our results indicate that TNF is expressed in ischemic neurons, astrocytes, microglia, endothelial cells, and in infiltrating polymorphonuclear leukocytes. Moreover, the onset of cerebral ischemia enhanced the expression of both the p55 and the p75 TNF receptors, suggesting that cytotoxic activities of TNF might be mediated through both increased synthesis of the cytokine and up-regulated expression of one or both receptors.
Permanent focal cerebral ischemia was performed as described elsewhere (33,34). Briefly, male Lewis rats were anesthetized with ketamine and both common carotid arteries were exposed and ligated. The entire temporalis muscle was removed and the bone adjacent to the zygomatic arch was drilled to open the surface of the brain. The middle cerebral artery was permanently occluded by electrocoagulation. After that, the contralateral common carotid artery (CCA) was occluded for 1 hr while the ipsilateral one was permanently ligated. Temperature was maintained at about 37°C. After 1 hr, the temporary occlusion of the CCA was removed and the neck and head incisions were closed. The animal was then allowed free access to food and water.
At different times (2–24 hr) after the onset of MCA occlusion, animals were deeply anesthetized and perfused as described by Breder et al. (35). Briefly, 30 ml of saline (pH 7.4) was perfused transcardially followed by 100 ml of 4% formaldehyde in phosphate-buffered saline (PBS) (pH 6.5) and 100 ml of the same fixative at pH 8.5. Animals were allowed to postfix for 30 min, then perfused with 50 ml of 20% sucrose solution in 0.1 M PBS (pH 7.4). Tissues of interest were removed and kept in sucrose solution overnight at 4°C. Sections (10 µm thick) were cut on a cryostat and air-dried for 1 hr. Adjacent sections were used for immunocytochemical and histological staining.
To study TNF receptor expression, fresh frozen brain sections were fixed in absolute methanol at −20°C.
Sections were incubated in a solution containing 0.3% H202 and 0.3% Triton X-100 in 0.01 M PBS for 10 min at room temperature. Washed sections were then incubated in a blocking solution containing 1% BSA, 5% normal goat serum, and 0.3% Triton X-100 in 0.01 M PBS for 1 hr at room temperature (RT) and then incubated for 24 hr at 4°C with a 1:100 dilution of the monoclonal hamster anti-murine TNF or monoclonal hamster anti-mouse TNF receptor (p55 or p75) antibodies (Genzyme) with 0.3% Triton X-100 and 0.1% BSA and 3% normal serum in 0.01 M PBS. Washed sections were incubated for 1–2 hr RT in 0.5% biotinilated anti-hamster IgG (Vector Labs) or biotinilated anti-Armenian hamster IgG (Jackson Immunoresearch Lab) for 1–2 hr. The reaction product was vizualized with 0.01% hy-drogen peroxide and 0.05% diaminobenzidine (DAB) as a chromogen. Sections were then processed for light microscopy by standard methods.
For detection of possible colocalization of TNF and TNFR immunoreactivity (IR) with particular cell types, double-label immunofluorescence was used. After incubation in a blocking solution, brain sections were incubated in a mixture of the diluted primary antibodies: hamster anti-TNF, or anti-p55 or anti-p75 with rabbit anti-glial fibrillary acidic protein (GFAP) (DAKO) or rabbit anti-neurofilament 200 (NF200). As secondary antibodies, a mixture of a rhodamine-conjugated goat anti-hamster IgG and fluore-scein-conjugated goat anti-rabbit IgG (Vector Lab) was used. After 2 hr of incubation with the secondary antibodies, the sections were processed for microscopic analysis with epifluores-cence according to standard processes. Specificity was determined by incubation of tissue without primary antibodies or by preabsorption of anti-TNF antibodies with recombinant mouse TNF (Genzyme).
We used a terminal deoxynucleotidyltransferase (TdT)-mediated dUTP-biotin nick end-labeling (TUNEL) method (ApopTag kit, Oncor) for specific staining of DNA fragmentation in apoptotic cells. Ten micrometer-thick brain sections obtained as described above were post-fixed in eth-anol-acetic acid (2:1) for 5 min at −20°C and washed with 0.01 M PBS three times for 5 min. After digesting protein in tissue sections using proteinase K (20 µg/ml) for 15 min at room temperature, and quenching endogenous peroxidase activity with 1% H2O2 in PBS for 5 min at room temperature, slides were placed in equilibration buffer and then incubated with working-strength TdT enzyme for 1 hr at 37°C. After 10 min of incubation in stop/wash buffer and washing in PBS, sections were incubated for 30 min with anti-digoxigenin-peroxidase, washed again, and reacted with diaminobenzidine. As a negative control, we used section incubated with a reaction buffer and distilled water instead of TdT enzyme. Double immunofluorescent labeling was performed on the same brain sections after the visualization of TUNEL-positive cells.
Neuronal and Glial Expression of TNF
Inflammatory Cell Expression of TNF
Expression of TNF Receptors
In double immunofluorescent-stained material from the core and penumbra sampled at 24 hr after the onset of ischemia, both TNF receptors colocalized with NF200 IR. No correlation of immunoreactive p55 or p75 proteins with GFAP ER was detected in association with hypertrophic astrocytic cell bodies in the ischemic penumbra, nor was it found within the ischemic core. p55 and p75 immunoreactivity was associated with GFAP IR, but not with NF200 IR, at the cortical surface, in association with brain capillary walls, and on the ventricular surface. Non capillary brain vessels also expressed p55 and p75 IR at their parenchymal surface, but there was no GFAP-positive staining associated with these larger vessels.
Colocalization of Neuronal TNF IR with TUNEL Labeling
This study presents the first evidence that multiple cell types express TNF and TNF receptors (p55 and p75) in ischemic brain cortex in response to experimental MCA occlusion. Our results further indicate that TNF expression in cerebral ischemia is not an exclusive feature of the neuronal cell population. Using morphological criteria, as well as double immunolabeling with antibodies against TNF and different cell markers, we identified a number of additional cell types expressing TNF after focal cerebral ischemia: astrocytes, microglia, choroid plexus cells, endothelial cells, PMNs, and possibly, pericytes. The level of TNF IR within neuronal somata was maximal by 6 hr after MCA occlusion and decreased by 24 hr. At 2 hr after the onset of ischemia, TNF IR was absent or ininimal within the developing infarct. These results agree with prior reports showing that maximal TNF protein expression occurred at 8–18 hr after brain lesioning (3), and with the observation that TNF mRNA expression in rat cerebral cortex was maximal between 6 and 12 hr after MCA occlusion (2). An earlier time course was shown by Buttini et al. (1), during which the peak level of TNF mRNA expression was at 3 hr after the onset of ischemia.
In addition to neurons, several types of activated microglial cells express TNF IR in association with focal cerebral ischemia. Transient ischemia (36–38), and soma-induced seizures (39) produce rapid (within 1–4 hr) activation of microglia which is most prominent adjacent to neurons that were destined to die (36,39). At 6–24 hr after the onset of ischemia, we found here that virtually all activated microglial cells were in close proximity to TNF-expressing neurons. Moreover, we have found a straight correlation between TNF expression and apoptosis within particular neurons at 24 hr after the MCA occlusion: only TUNEL-positive apoptotic neurons expressed TNF IR. These findings are in agreement with the classical viewpoint that neurodegenerative events can signal resting microglia, transforming them into an active form. Although no direct TNF toxicity on neurons was shown (2,9,40,41), there are several observations that TNF can act selectively, destroying diseased cells or those treated with protein synthesis inhibitors (42,43), with little effect on normal cells (ref. from 44). Thus, as TNF increases during ischemia, brain damage increases (9,10).
In response to focal ischemia, some cells displayed a patchy distribution of TNF IR restricted to the cell margin. The multifunctional activities of TNF are thought to be mediated through two molecular forms—a 17-kD mature form and a transmembrane 26-kD precursor protein. TNF IR observed at the periphery of cells may represent this transmembrane form of TNF. TNF signaling via the 26-kD transmembrane form has been associated with contact-dependent lymphocyte and monocyte-mediated cell killing (45), polyclonal B cell activation (46), and localized tissue toxicity (47).
We found that permanent MCA occlusion induced expression of TNF IR in hypertrophic astrocytes within the ischemic penumbra. This observation is in agreement with other experiments using cultured astrocytes. For instance, TNF mRNA expression is markedly elevated in response to exogenous lipopolysaccharide (LPS) (20). Furthermore, the TNF produced by LPS-stimulated astrocyte cultures has been shown to be cytotoxic for oligodendrocytes (48). It has also been reported that reactive astrocytes from the brains of patients with multiple sclerosis are positive for TNF IR (49). Our visualization of dense, patchy TNF IR at neuronal cell margins might represent either TNF within the end-feet of reactive astrocytes which intimately surround neuronal cell bodies, or neuron-associated transmembrane TNF, or both.
The leukocyte infiltration that we observed by 24 hr after the onset of ischemia is a well-known hallmark of CNS inflammation. In the case of brain ischemia, this process is led by polymorphonuclear leukocytes. Infiltration of the brain parenchyma by PMNs from the circulation has been demonstrated in several different animal models of stroke (50,51), and specific adhesion molecules (e.g., ICAM-1, ICAM-2, and ELAM-1) responsible for leucocyte infiltration have been defined. The significance of this inflammatory response in ischemic injury has recently been demonstrated (52–54) since monoclonal antibodies against ICAM-1 significantly reduce ischemic brain damage. In vitro, PMNs cultured from blood can produce TNF mRNA and protein (55). Our results have demonstrated that infiltrating PMN leukocytes strongly expressed TNF IR within ischemic brain tissue. The early appearance of TNF expression (near maximal level by about 6 hr after MCA occlusion; ref. 2 and our results) versus the later appearance of recruited leukocytes suggests that locally produced TNF occurs prior to PMN infiltration. The reinforcement of TNF expression by strongly TNF-expressing infiltrating PMNs might then further contribute to brain damage in stroke. This suggestion is in agreement with the recent demonstration that depletion of leukocytes provides protection against ischemic brain damage (56,57), although other locally produced cyto-toxins undoubtedly play a role.
After MCA occlusion, TNF IR was apparent both perivascularly as well as within endothelial cells associated with brain vasculature. Although we can not exclude the possibility that perivascular TNF IR might be partially contributed by pericytes, it seems likely that perivascular TNF is present in astroglial end-feet, which are similarly distributed to surround capillaries but not larger vessels.
The present studies showed that permanent MCA occlusion induced marked up-regulation of p55 and p75 TNF receptor protein expression within ischemic cortex, but with different kinetics and distinct cellular distributions. p55-associated IR, for instance, was significantly up-regulated by 6 hr after the onset of ischemia, whereas increased p75 IR was not observed until 24 hr. Overall, p55 IR was significantly more abundant than p75 IR during brain ischemia. There is a large body of evidence indicating that TNF cytotoxicity is mediated largely or entirely by p55. The observed up-regulation of this TNF receptor, together with the dramatic up-regulation of its ligand, favor an injurious role of TNF during stroke (10).
Although most cells express TNF receptors in vitro, expression of the TNFR genes is differentially regulated in different tissues in vivo (see ref. 26). It has been shown recently that normal astrocytes and glioblastoma cell lines express both p55 mRNA and p75 mRNA (31,36). The absence of p55 IR and p75 IR within GFAP-positive cell bodies ipsilateral to the induced stroke has several possible explanations: (a) a lack of TNF receptor expression by astrocytes during ischemia; (b) a low level of expression that was undetected by double immunofluorescence; and (c) subcellular distribution of receptor proteins via astrocytic processes to the end-feet regions. A combination of the latter two explanations seems consistent with the lack of GFAP/TNFR double-positive cell bodies despite prominent colocalization of p55 and p75 IR with GFAP IR on the brain and ventricular surfaces, as well as on the cortical capillaries, where astrocytic end-feet form an enveloping layer.
The appearance of both TNF receptors on the inner surface of brain vessel as well as abundunt punctate p55 IR and, to a lesser extent, p75 IR product within ischemic cortex after MCA occlusion might also reflect the extensive induction of soluble TNF receptors. This suggestion is in agreement with data showing that soluble receptors for TNF are highly inducible and can prevent the adverse pathologic sequelae caused by the high level of TNF production in lethal sepsis (59), trauma (60), and stroke (9,11,12). TNFRs are also constitutively shed in substantial amounts in vivo, thus plausibly regulating TNF activity (61). The granule- and dot-like p55 and p75 immunoreactivity we observed during stroke may be the result of increased TNF receptor shedding. The appearance of p55 and p75 immunoreactive granules on the cell surface might reflect not only the up-regulation of membrane-associated receptor expression in response to the MCA occlusion but also receptor aggregation in response to ligand binding (62).
The biological role of TNF in cerebral ischemia is probably dependent upon a balance in signaling via both p55 and p75, but it is not yet clear what the consequences of these molecular interactions will be for the ischemic brain. It has been reported in cultured neuronal cells that TNF can be either neurotrophic or neurotoxic, depending on unidentified factors in the culture conditions (63,64). Some authors have found no direct TNF toxicity on neurons (2,9,40,41), but other observations suggest that TNF can act selectively, destroying diseased or otherwise stressed cells (42,43), while having no effect on normal cells (44). Our results clearly show strongly induced TNF expression by 6 hr after permanent MCA occlusion, preceding the period of extensive brain cell death. It is likely therefore that TNF mediates cellular damage and toxicity in stroke. This suggestion is supported by recent evidence showing the neuroprotective effects of TNF inhibition in experimental ischemia by administrating neutralizing anti-TNF antibodies, or a tetravalent guanylhydrazone inhibitor of TNF synthesis (CNI-1493), either of which significantly reduce infarct volume (10). Inhibition of TNF protects against the development of cerebral edema (9,65) and soluble TNFR1 administration is neuroprotective (9,11,12). It now appears that the enhanced production of TNF and its receptors on glial, neuronal and peripheral inflammatory cells occupies a pivotal role in mediating the injurious effects of brain ischemia.
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