Cytokines are thought to be important mediators in physiologic and pathophysiologic processes affecting the central nervous system (CNS). To explore this hypothesis, transgenic mice were generated in which the cytokine interleukin 6 (IL-6), under the regulatory control of the glial fibrillary acidic protein gene promoter, was overexpressed in the CNS. A number of transgenic founder mice and their offspring exhibited a neurologic syndrome the severity of which correlated with the levels of cerebral IL-6 expression. Transgenic mice with high levels of IL-6 expression developed severe neurologic disease characterized by runting, tremor, ataxia, and seizure. Neuropathologic manifestations included neurodegeneration, astrocytosis, angiogenesis, and induction of acute-phase-protein production. These rmdings indicate that cytokines such as IL-6 can have a direct pathogenic role in inflammatory, infectious, and neurodegenerative CNS diseases.

In a lethal West Nile virus (WNV) model, central nervous system infection triggered a threefold increase in CD45 int /CD11b + /CD11c ؊ microglia at days 6 -7 postinfection (p.i.). Few microglia were proliferating, suggesting that the increased numbers were derived from a migratory precursor cell. Depletion of " circulating " (Gr1 ؊ (Ly6C lo )CX3CR1 + ) and " infl ammatory " (Gr1 hi /Ly6C hi /CCR2 + ) classical monocytes during infection abrogated the increase in microglia. C57BL/6 chimeras reconstituted with cFMS -enhanced green fl uorescent protein (EGFP) bone marrow (BM) showed large numbers of peripherally derived (GFP + ) microglia expressing GR1 + (Ly6C + ) at day 7 p.i., suggesting that the infl ammatory monocyte is a microglial precursor. This was confi rmed by adoptive transfer of labeled BM (Ly6C hi /CD115 + ) or circulating infl ammatory monocytes that traffi cked to the WNV-infected brain and expressed a microglial phenotype. CCL2 is a chemokine that is highly expressed during WNV infection and important in infl ammatory monocyte traffi cking. Neutralization of CCL2 not only reduced the number of GFP + microglia in the brain during WNV infection but prolonged the life of infected animals. Therefore, CCL2-dependent infl ammatory monocyte migration is critical for increases in microglia during WNV infection and may also play a pathogenic role during WNV encephalitis.

Postnatal neurogenesis can be modulated after brain injury, but the role of the attendant expression of inflammatory mediators in such responses remains to be determined. Here we report that transgenically directed production of interleukin-6 (IL-6) by astroglia decreased overall neurogenesis by 63% in the hippocampal dentate gyrus of young adult transgenic mice. The proliferation, survival, and differentiation of neural progenitor cells labeled with the thymidine analog bromodeoxyuridine were all reduced in the granule cell layer of these mice, whereas their distribution and gliogenesis appeared normal. These effects were not a consequence of general toxicity of the IL-6 transgene, because they were manifested in the absence of neuronal death and of major changes in glial cell number and morphology. These findings suggest that long-term exposure of the brain to proinflammatory mediators such as IL-6, as is seen in certain degenerative disorders and infections, can interfere with adult neurogenesis.

Infection of C57BL/6 mice with mouse hepatitis virus (MHV) results in a demyelinating encephalomyelitis characterized by mononuclear cell infiltration and white matter destruction similar to the pathology of the human demyelinating disease multiple sclerosis. The contributions of CD4 ؉ and CD8 ؉ T cells in the pathogenesis of the disease were investigated. Significantly less severe inflammation and demyelination were observed in CD4؊/؊ mice than in CD8 ؊/؊ and C57BL/6 mice (P < 0.002 and P < 0.001, respectively). Immunophenotyping of central nervous system (CNS) infiltrates revealed that CD4؊/؊ mice had a significant reduction in numbers of activated macrophages/microglial cells in the brain compared to the numbers in CD8 ؊/؊ and C57BL/6 mice, indicating a role for these cells in myelin destruction. Furthermore, CD4 ؊/؊ mice displayed lower levels of RANTES (a C-C chemokine) mRNA transcripts and protein, suggesting a role for this molecule in the pathogenesis of MHV-induced neurologic disease. Administration of RANTES antisera to MHV-infected C57BL/6 mice resulted in a significant reduction in macrophage infiltration and demyelination (P < 0.001) compared to those in control mice. These data indicate that CD4 ؉ T cells have a pivotal role in accelerating CNS inflammation and demyelination within infected mice, possibly by regulating RANTES expression, which in turn coordinates the trafficking of macrophages into the CNS, leading to myelin destruction.Demyelination is a complex neuropathological process in which the myelin sheath that insulates and protects axons is damaged or destroyed. Several animal models of demyelination have been developed that have provided valuable contributions to the understanding of the immunopathological events that may drive human demyelinating diseases such as multiple sclerosis (MS) (22,31). Among these is the neurotropic mouse hepatitis virus (MHV) model of virus-induced demyelination (12,18). MHV is a positive-strand RNA virus that causes a variety of clinical diseases in susceptible strains of mice (23). Neurovirulent strains of MHV cause an acute encephalomyelitis that may ultimately progress to demyelinating disease characterized clinically by abnormal gait and hind-limb paralysis. Histologically, affected animals exhibit mononuclear cell infiltration and myelin destruction. Early studies suggested that the demyelination observed in MHV-infected mice was the result of virus-induced damage or destruction of oligodendrocytes (9, 36). However, more recent reports have indicated that MHV-induced demyelination is more complex and may also involve immunopathologic responses against viral antigens expressed in infected tissues (5, 35).As T cells are considered central to the development of demyelinating lesions in animal models of demyelination as well as MS, it is imperative to better understand the mechanisms by which these cells exert their pathological effect (24, 25). We sought to evaluate the contributions of CD4 ϩ and CD8 ϩ T cells in MHV-induced central nervous system (CNS) d...

International audienceA core flow test autoclave has been designed in order to reproduce an injection well at a scale of 1/20. This autoclave allows the CO2 injection into a steel tube cemented to a core sample of red sandstone from the Triassic formations of Lorraine (France). Temperature and pressure gradients can be recorded between the injection point and the confining water phase. Such gradients imply solubility gradients of CO2 and mineral species into the water phase as permeability changes with time. Some chemical reactions can be observed from collected sample at the end of the experiment. Precipitation and dissolution are suspected both into the cement and rock phases. No fracturing is observed. Cement-rock interface is not opened

Inflammatory monocyte-derived effector cells play an important role in the pathogenesis of numerous inflammatory diseases. However, no treatment option exists that is capable of modulating these cells specifically. We show that infused negatively charged, immune-modifying microparticles (IMPs), derived from polystyrene, microdiamonds, or biodegradable poly(lactic-co-glycolic) acid, were taken up by inflammatory monocytes, in an opsonin-independent fashion, via the macrophage receptor with collagenous structure (MARCO). Subsequently, these monocytes no longer trafficked to sites of inflammation; rather, IMP infusion caused their sequestration in the spleen through apoptotic cell clearance mechanisms and, ultimately, caspase-3–mediated apoptosis. Administration of IMPs in mouse models of myocardial infarction, experimental autoimmune encephalomyelitis, dextran sodium sulfate–induced colitis, thioglycollate-induced peritonitis, and lethal flavivirus encephalitis markedly reduced monocyte accumulation at inflammatory foci, reduced disease symptoms, and promoted tissue repair. Together, these data highlight the intricate interplay between scavenger receptors, the spleen, and inflammatory monocyte function and support the translation of IMPs for therapeutic use in diseases caused or potentiated by inflammatory monocytes.

Inf lammation with expression of interleukin 6 (IL-6) in the brain occurs in many neurodegenerative disorders. To better understand the role of IL-6 in such disorders, we examined performance in a learning task in conjunction with molecular and cellular neuropathology in transgenic mice that express IL-6 chronically from astrocytes in the brain. Transgenic mice exhibited dose-and age-related deficits in avoidance learning that closely corresponded with specific progressive neuropathological changes. These results establish a link between the central nervous system expression of IL-6, inf lammatory neurodegeneration, and a learning impairment in transgenic mice. They suggest a critical role for a proinf lammatory cytokine in the cognitive deficits and associated neuroinf lammatory changes that have been documented in neurodegenerative diseases such as Alzheimer disease and AIDS.

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