Evolution of Neuropathologic Abnormalities Associated with Blood-Brain Barrier Breakdown in Transgenic Mice Expressing lnterleukin-6 in Astrocytes

Brett, Francesca; Mizisin, Andrew P.; Powell, Henry C.; Campbell, Iain L.

doi:10.1097/00005072-199511000-00003

Cited by 187 publications

(119 citation statements)

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“…Similar changes were seen in the medulla (blood vessel density decreased to 78±4.8% of wild-type brain in GFAP-IFNα mice (p<0.05) and increased to 132±8.9% of wild-type brain in GFAP-IL6 transgenic mice (p<0.05)). These changes in vascular density are consistent with previous observations in these transgenic mice strains, detailing vascular degeneration and dilatation in the brain of GFAP-IFNα mice (Akwa et al 1998), and proliferative angiopathy in the brains of GFAP-IL6 mice (Campbell et al 1993;Brett et al 1995). With this information in hand, we conclude that while immunohistochemistry shows that cerebral blood vessels in the GFAP-IFNα mice express increased levels of α6 integrin per blood vessel (Figure 1), the reduced blood vessel density in the brain of these mice will tend to mask this effect, so that the total level of α6 integrin present in the brain shows no apparent difference from the wild-type.…”

Section: Cerebral Blood Vessels In Transgenic Mice Expressing Il-6 Orsupporting

confidence: 92%

Increased expression of the β4 and α5 integrin subunits in cerebral blood vessels of transgenic mice chronically producing the pro-inflammatory cytokines IL-6 or IFN-α in the central nervous system

Milner

Campbell

2006

Molecular and Cellular Neuroscience

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Evidence suggests that vascular function is strongly regulated by extracellular matrix (ECM) proteins via integrin-mediated signaling. To determine whether integrin expression on cerebral blood vessels is altered during chronic neuroinflammation, we examined β1 and β4 integrin expression in transgenic mice with astrocyte production of the pro-inflammatory cytokines interleukin-6 (IL-6) or interferon-α (IFN-α). Chronic production of IL-6 or IFN-α in the CNS promoted vascular expression of the β4 and α5 integrin subunits, and this was contributed mostly by astrocytes. Vascular expression of the ECM ligands laminin and fibronectin was also increased. Cell culture studies showed that astrocyte expression of the β4 and α5 integrins was significantly upregulated by IL-6 and IFN-α respectively, while endothelial expression of these integrins was unchanged. These results show that astrocytes respond to IL-6 and IFN-α by upregulating integrin expression. We propose that during neuroinflammation, astrocytes attempt to increase adhesive interactions at the blood-brain barrier (BBB), in order to increase barrier integrity.

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Section: Cerebral Blood Vessels In Transgenic Mice Expressing Il-6 Orsupporting

confidence: 92%

Increased expression of the β4 and α5 integrin subunits in cerebral blood vessels of transgenic mice chronically producing the pro-inflammatory cytokines IL-6 or IFN-α in the central nervous system

Milner

Campbell

2006

Molecular and Cellular Neuroscience

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“…TNF-␣ has been shown to facilitate the entry of WNV to the CNS by breaching the blood-brain barrier (36). Although we have previously shown that IL-6-deficient mice do not show a difference in WNV susceptibility (36), the elevated level of IL-6 in the elderly could contribute to neuronal injury within the central nervous system in humans (3).…”

Section: Discussionmentioning

confidence: 82%

“…Viral stocks were 6.3 ϫ 10 8 /ml for the NY99-E154 culture. To obtain a multiplicity of infection (MOI) of 1, 1 ϫ 10 6 viral particles were used to infect the same number of macrophages in a 35-mm 3 well in a total volume of 2 ml of culture medium. All studies with WNV were conducted in a biosafety level 3 facility, licensed according to the regulations of the state of Connecticut and the Office of Environmental Health and Safety of Yale University.…”

mentioning

confidence: 99%

Dysregulation of TLR3 Impairs the Innate Immune Response to West Nile Virus in the Elderly

Kong

Delroux

Wang

et al. 2008

J Virol

162

180

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West Nile virus (WNV), a mosquito-borne flavivirus, has recently emerged in North America, and the elderly are particularly susceptible to severe neurological disease and death from infection with this virus. We have investigated the innate immune response of primary human macrophages to WNV in vitro and have found significant differences between the responsiveness of macrophages derived from younger donors and that from older donors. Binding of the glycosylated WNV envelope protein to the C-type lectin dendritic cell-specific intercellular adhesion molecule 3 (ICAM3) grabbing nonintegrin (DC-SIGN) leads to a reduction in the expression of Toll-like receptor 3 (TLR3) in macrophages from young donors via the signal transducer and activator of transcription 1 (STAT1)-mediated pathway. This signaling is impaired in the elderly, and the elevated levels of TLR3 result in an elevation of cytokine levels. This alteration of the innate immune response with aging may contribute to the permeability of the blood-brain barrier and suggests a possible mechanism for the increased severity of WNV infection in older individuals.

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“…It has been shown that maternal endotoxin administration induces a dosedependent cytokine increase in the fetal rat brain (32). In several animal models IL-6 was able to affect the integrity of the blood-brain barrier and to induce brain injury (33)(34)(35). In preterm infants a breakdown of a still immature blood-brain barrier may be important in the pathophysiology of the dreaded complication of intraventricular hemorrhage.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Interleukin-6 and Interleukin-8 Synthesis in Term and Preterm Infants

et al. 2002

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There is growing evidence that sepsis-related complications in neonates are crucially mediated by the action of proinflammatory cytokines. It has previously been demonstrated that elevated IL-6 and IL-8 levels can predict brain damage and chronic lung disease in preterm infants. However, it is the current view that neonates have a reduced capability to produce proinflammatory cytokines. To clarify this issue, we analyzed the inflammatory response in term and preterm infants directly at the single cell level by flow cytometry. Endotoxin challenge was performed under defined conditions on monocytes obtained from 50 healthy adults and 119 neonates, which consist of 45 term infants, 63 preterm infants (26.1-36.7 wk of gestational age), and 11 preterm infants with proven infection (24.6 -29.9 wk). Our results challenge the existing view of an immature inflammatory response by demonstrating that term infants and preterm infants display a higher percentage of IL-6 -and IL-8 -positive cells than adults. After preincubation with dexamethasone the number of cytokine-positive cells decreased in all groups, but the number of IL-8 -positive cells remained higher in term and preterm infants Ͼ32 wk compared with adults. These observations demonstrate not only a well-developed but also an enhanced inflammatory response in term and preterm infants. Under consideration of several detrimental effects of IL-6 and IL-8, our data may have major implications on the pathophysiology of inflammatorytriggered neonatal diseases. Neonatal bacterial sepsis remains a critical determinant of outcome in infants of very low birth weight despite the availability of antibiotics (1-3). The immaturity of the neonatal immune system, especially a reduced cytokine-producing capacity, was assumed to be responsible for the high susceptibility to infections (4 -11). Particularly, the high prevalence of complications secondary to infections represents a major determinant of neonatal mortality and morbidity (3). Although older children and adults are usually able to restrict bacterial infections, neonates often develop a severe systemic inflammatory response with detrimental effects. There is growing evidence that this process is crucially mediated by the action of distinct inflammatory cytokines (12, 13). It has previously been demonstrated that elevated IL-6 and IL-8 levels in cord blood and lung lavage can predict neonatal brain damage and chronic lung disease in preterm infants (14 -16). Furthermore, proinflammatory cytokines could be demonstrated in high amounts in brain white matter lesions of preterm infants (17). These observations strongly suggest a key role of proinflammatory cytokines in the pathogenesis of several neonatal diseases. Although a variety of studies have been performed on inflammatory mediators in neonates during infection, these data can be misleading because of the evolving immunoparalysis occurring in progressing sepsis (18,19). To better characterize the inflammatory response in neonates we performed an ex vivo model of sepsis, ...

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Evolution of Neuropathologic Abnormalities Associated with Blood-Brain Barrier Breakdown in Transgenic Mice Expressing lnterleukin-6 in Astrocytes

Cited by 187 publications

References 0 publications

Increased expression of the β4 and α5 integrin subunits in cerebral blood vessels of transgenic mice chronically producing the pro-inflammatory cytokines IL-6 or IFN-α in the central nervous system

Increased expression of the β4 and α5 integrin subunits in cerebral blood vessels of transgenic mice chronically producing the pro-inflammatory cytokines IL-6 or IFN-α in the central nervous system

Dysregulation of TLR3 Impairs the Innate Immune Response to West Nile Virus in the Elderly

Enhanced Interleukin-6 and Interleukin-8 Synthesis in Term and Preterm Infants

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