Interleukin‐1β does not induce reactive astrogliosis, neovascularization or scar formation in the immature rat brain

Sievers, Jobst; Struckhoff, Gernot; Puchner, M. J. A.

doi:10.1016/0736-5748(93)90086-s

Cited by 13 publications

(5 citation statements)

References 30 publications

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“…Giulian et al (193) showed that IL-1b regulates astrocytic growth, and GM-CSF is a potent microglial mitogen that regulates microglial component of glial scars, suggesting that inflammation stimulates gliosis. Sievers et al (512), however, found that application of IL-1b does not induce reactive astrogliosis, neovascularization, or scar formation in immature rat brains. The glucocorticoid drug methylprednisolone (MP) is a potent anti-inflammatory drug that suppresses IL-1 expression.…”

Section: The Glial Scar Theorymentioning

confidence: 97%

Spinal Cord Regeneration

Young

2014

Cell Transplant

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Three theories of regeneration dominate neuroscience today, all purporting to explain why the adult central nervous system (CNS) cannot regenerate. One theory proposes that Nogo, a molecule expressed by myelin, prevents axonal growth. The second theory emphasizes the role of glial scars. The third theory proposes that chondroitin sulfate proteoglycans (CSPGs) prevent axon growth. Blockade of Nogo, CSPG, and their receptors indeed can stop axon growth in vitro and improve functional recovery in animal spinal cord injury (SCI) models. These therapies also increase sprouting of surviving axons and plasticity. However, many investigators have reported regenerating spinal tracts without eliminating Nogo, glial scar, or CSPG. For example, many motor and sensory axons grow spontaneously in contused spinal cords, crossing gliotic tissue and white matter surrounding the injury site. Sensory axons grow long distances in injured dorsal columns after peripheral nerve lesions. Cell transplants and treatments that increase cAMP and neurotrophins stimulate motor and sensory axons to cross glial scars and to grow long distances in white matter. Genetic studies deleting all members of the Nogo family and even the Nogo receptor do not always improve regeneration in mice. A recent study reported that suppressing the phosphatase and tensin homolog (PTEN) gene promotes prolific corticospinal tract regeneration. These findings cannot be explained by the current theories proposing that Nogo and glial scars prevent regeneration. Spinal axons clearly can and will grow through glial scars and Nogo-expressing tissue under some circumstances. The observation that deleting PTEN allows corticospinal tract regeneration indicates that the PTEN/AKT/mTOR pathway regulates axonal growth. Finally, many other factors stimulate spinal axonal growth, including conditioning lesions, cAMP, glycogen synthetase kinase inhibition, and neurotrophins. To explain these disparate regenerative phenomena, I propose that the spinal cord has evolved regenerative mechanisms that are normally suppressed by multiple extrinsic and intrinsic factors but can be activated by injury, mediated by the PTEN/ AKT/mTOR, cAMP, and GSK3b pathways, to stimulate neural growth and proliferation.

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Section: The Glial Scar Theorymentioning

confidence: 97%

Spinal Cord Regeneration

Young

2014

Cell Transplant

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“…First, the dose of IL-6 produced by the transgene at this age may be below the threshold needed to activate the cells. Second, the neonatal astrocyte might be function ally immature and unable to respond to the IL-6 [47][48][49]. Third, we analyzed total brain mRNA and therefore cannot rule out the possibility that there were small region-specific increases in the GFAP expression.…”

Section: Discussionmentioning

confidence: 99%

Reactive Gliosis as a Consequence of Interleukin-6 Expression in the Brain: Studies in Transgenic Mice

Chiang

Stalder²,

Samimi³

et al. 1994

Dev Neurosci

227

134

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Gliosis is a characteristic pathologic state in many CNS disorders. Cytokines are considered to be effectors of gliosis. In order to explore the role of IL-6 in gliosis, the temporal and spatial expression of the IL-6 gene and its consequent effects on the brain were studied in a GFAP-IL6 transgenic mouse model. In GFAP-IL6 mice, IL-6 transgene expression was detectable in the brain at 1 week postnatally and increased to maximal levels by 3 months of age before declining at 8 and 12 months. Enhanced glial fibrillary acidic protein (GFAP) (marker for astrocytes) and Mac-I (marker for microglia) mRNA expression were first prominent at 1 month, increased to maximum levels by 3 months and remained significantly elevated through 12 months of age. Western blot analysis revealed that the enhanced GFAP mRNA expression in these transgenic mice was accompanied by increased GFAP protein levels. Immunostaining for Mac-I demonstrated that in addition to an increased staining intensity, the number of cells expressing the microglial/macrophage marker was also apparently increased, particularly in the cerebellum and brain stem. Concurrent with IL-6 transgene mRNA expression and reactive gliosis, upregulation of IL-1α/β, TNFα, ICAM-1 and EB22/5.3 (acute-phase reactant) but not inducible nitric oxide synthase gene expression was also observed. EB22/5.3 mRNA expression was most prominent and increased progressively with age. Expression of the IL-6, GFAP and EB22/5.3 RNAs was found to have similar distribution in the brain being found predominantly in the cerebellum, brain stem and sub-cortical regions. In conclusion, the constitutive expression of IL-6 in the brain induced the development of a pronounced and lifelong reactive gliosis affecting both astrocytes and microglia. The altered state of these cells may contribute to the functional and structural CNS impairment exhibited by the GFAP-IL6 mice. Finally, in these mice, expression of the EB22/5.3 gene correlated closely with the progression of neuropathy indicating that this acute-phase response gene was a good marker for and may be involved in the pathogenesis of CNS injury mediated by the expression of IL-6.

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“…5,28,37 In immature animals, no astroglial scar forms due to the lack of a meningeal invasion. 3,5,6,16,39 This demonstrates the importance of meningeal cells for the formation of the glia limitans; it, however, leads to the question of why meningeal cells migrate into the lesion only in adult and not in immature animals. An understanding of the difference between the formation of the accessory and superficial glial membrane is of great interest since the establishment of a glial cicatrix is thought to be an impediment to regenerating axons, 19,35,36 and a comprehension of this process possibly allows one to interfere with cicatrization and provide regenerating axons with a more favorable environment.…”

mentioning

confidence: 99%

Cocultures of meningeal and astrocytic cells—A model for the formation of the glial‐limiting membrane

Struckhoff

1995

Intl J of Devlp Neuroscience

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The glial-limiting membrane at the border of the central nervous system (CNS) consists of glial endfeet covered by a basal lamina. The formation of the glia limitans seems to be controlled by adjacent meninges but only little is known about this interaction. In the present study astrocytes and meningeal cells were investigated in vitro to see if cocultures of these cells can serve as a suitable model for the differentiation of the glial-limiting membrane and can be used to define the conditions under which the glial-limiting membrane develops. The following observations were made in cocultures of meningeal and astrocytic cells of two-day-old rats: (i) epithelioid astrocytes were transformed into stellate cells; (ii) single colonies of proliferating epithelioid astrocytes were generated; (iii) the area around these colonies becomes devoid of meningeal cells, which seem to form a circular border around the astroglial islands; (iv) from the glial colonies long thin glial processes grow towards the surrounding meningeal cells, terminating at the site of contact; (v) in the contact zone between meningeal cells and astrocytes irregular shaped deposits of electron dense material resembling a basal lamina were seen. These observations indicate that indeed a structure resembling a glial-limiting membrane develops in cocultures of meningeal and astrocytic cells. Its formation depends on the balance of growth promoting effects of meningeal cells on astrocytes and growth inhibiting effects of astrocytes on meningeal cells. Both activities can be enriched from conditioned media of pure astrocytic or meningeal cell culture. The proposed model of meningo-astrocytic cocultures may be a helpful instrument for further investigations on the formation of the glia limitans.

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Interleukin‐1β does not induce reactive astrogliosis, neovascularization or scar formation in the immature rat brain

Cited by 13 publications

References 30 publications

Spinal Cord Regeneration

Spinal Cord Regeneration

Reactive Gliosis as a Consequence of Interleukin-6 Expression in the Brain: Studies in Transgenic Mice

Cocultures of meningeal and astrocytic cells—A model for the formation of the glial‐limiting membrane

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