A dual role for microglia in promoting tissue inhibitor of metalloproteinase (TIMP) expression in glial cells in response to neuroinflammatory stimuli

<p>Abstract</p> <p>Background</p> <p>By neutralizing the effect of the matrix metalloproteinases (MMPs), the tissue inhibitors of matrix metalloproteinases (TIMPs) play a critical role in maintaining tissue proteolysis in balance. As the major reactive glial cell types in the central nervous system (CNS), microglia and astrocytes play fundamental roles in mediating tissue breakdown and repair. As such, it is important to define the TIMP expression profile in these cells, as well as the mechanisms of regulation by neuroinflammatory stimuli.</p> <p>Methods</p> <p>Primary mixed glial cultures (MGC), pure microglia, and pure astrocytes were used in this study. To study astrocytes, we employed a recently described pure astrocyte culture system, which has the major advantage of totally lacking microglia. The three different types of culture were treated with lipopolysaccharide (LPS) or individual cytokines, and cell culture supernatants assayed for TIMP-1 or TIMP-2 protein expression by western blot.</p> <p>Results</p> <p>LPS induced TIMP-1 expression in MGC, but not in pure astrocyte or microglial cultures. When pure astrocytes were treated with the cytokines IL-1β, IFN-γ, TNF or TGF-β1, only IL-1β induced TIMP-1 expression. Significantly, astrocyte TIMP-1 expression was restored in LPS-treated astrocyte cultures after the addition of microglia, or conditioned medium taken from LPS-activated microglia (MG-CM). Furthermore, this effect was lost after depletion of IL-1β from MG-CM. By contrast, TIMP-2 was constitutively expressed by astrocytes, whereas microglia expressed TIMP-2 only after exposure to serum.</p> <p>Conclusions</p> <p>Taken together, these results demonstrate an important concept in glial interactions, by showing that microglia play a central role in regulating glial cell expression of TIMPs, and identify microglial IL-1β as playing a key role in mediating microglial-astrocyte communication.</p

Níveis de aptidão física relacionada à saúde de escolares da zona urbana e rural de Santa Cruz do Sul – RS: estudo comparativo

Justificativa e objetivos: O presente estudo comparativo objetiva verificar se existem diferenças nos níveis de flexibilidade, resistência abdominal e aptidão cardiorrespiratória (APCR) de escolares da zona urbana e rural de Santa Cruz do Sul-RS. Métodos: A amostra é composta por 230 crianças e adolescentes, sendo 107 do sexo masculino, com idades entre 7 a 17 anos. Para avaliação do teste de flexibilidade, foi utilizado o banco de Wells. O nível de resistência abdominal foi avaliado através do número máximo de repetições em um minuto. Para avaliação de APCR, foi aplicado o teste de corrida/caminhada de 6 minutos. Resultados: Entre os meninos, resultados mais satisfatórios foram encontrados na escola municipal da zona rural, em comparação à escola estadual urbana, apresentando maiores níveis de flexibilidade (23,1 cm versus 18,7 cm; p=0,029) e de APCR (1534,9 m versus 1275,6 m; p=0,013) e IMC inferior (18,6 kg/m² versus 21,3 kg/m²; p=0,027). As meninas da escola municipal rural apresentaram melhores níveis de APCR em comparação às meninas da escola municipal urbana (1197,3 m versus 1084,1 m; p=0,006). Conclusões: Meninos da escola municipal rural apresentam melhores níveis de índice de massa corporal, flexibilidade e aptidão cardiorrespiratória, em comparação aos escolares da escola estadual urbana. As meninas da escola municipal rural apresentaram melhores níveis de aptidão cardiorrespiratória quando comparadas às alunas da escola municipal urbana

Tissue inhibitor of metalloproteinases-1 protects human neurons from staurosporine and HIV-1-induced apoptosis: mechanisms and relevance to HIV-1-associated dementia

HIV-1-associated dementia (HAD)-relevant proinflammatory cytokines robustly induce astrocyte tissue inhibitor of metalloproteinases-1 (TIMP-1). As TIMP-1 displays pleotropic functions, we hypothesized that TIMP-1 expression may serve as a neuroprotective response of astrocytes. Previously, we reported that chronically activated astrocytes fail to maintain elevated TIMP-1 expression, and TIMP-1 levels are lower in the brain of HAD patients; a phenomenon that may contribute to central nervous system pathogenesis. Further, the role of TIMP-1 as a neurotrophic factor is incompletely understood. In this study, we report that staurosporine (STS) and HIV-1ADA virus, both led to induction of apoptosis in cultured primary human neurons. Interestingly, cotreatment with TIMP-1 protects neurons from apoptosis and reverses neuronal morphological changes induced by these toxins. Further, the anti-apoptotic effect was not observed with TIMP-2 or -3, but was retained in a mutant of the N-terminal TIMP-1 protein with threonine-2 mutated to glycine (T2G) that is deficient in matrix metalloproteinase (MMP)-1, -2 and -3 inhibitory activity. Therefore, the mechanism is specific to TIMP-1 and partially independent of MMP-inhibition. Additionally, TIMP-1 modulates the Bcl-2 family of proteins and inhibits opening of mitochondrial permeability transition pores induced by HIV-1 or STS. Together, these findings describe a novel function, mechanism and direct role of TIMP-1 in neuroprotection, suggesting its therapeutic potential in HAD and possibly in other neurodegenerative diseases

Comparing Notes: Recording and Criticism

This chapter charts the ways in which recording has changed the nature of music criticism. It both provides an overview of the history of recording and music criticism, from the advent of Edison’s Phonograph to the present day, and examines the issues arising from this new technology and the consequent transformation of critical thought and practice

Wider Still and Wider: British Music Criticism since the Second World War

This chapter provides the first historical examination of music criticism in Britain since the Second World War. In the process, it also challenges the simplistic prevailing view of this being a period of decline from a golden age in music criticism

β4 integrin is not essential for localization of hemidesmosome proteins plectin and CD151 in cerebral vessels

Objective: In the central nervous system (CNS), β4 integrin is predominantly expressed by endothelial cells lining arterioles. As β4 integrin plays an essential role in epithelial tissues, organizing structural proteins into specialized adhesive structures called hemidesmosomes (HD), the aim of this study was to determine whether it plays a similar role in CNS endothelium. Methods: Dual-immunofluorescence was used to examine the relationship between β4 integrin expression and co-expression of the HD proteins plectin and CD151 in frozen sections of mouse brain, both under normoxic (control) conditions and following chronic mild hypoxia. The requirement of β4 integrin for the localization of HD proteins was examined in transgenic mice lacking β4 integrin expression specifically in endothelial cells (β4-EC-KO mice). Results: Immunofluorescence revealed that in the normal adult CNS, plectin and CD151 strongly co-localized with β4 integrin in arterioles. However, in the chronic mild hypoxia model, in which extensive cerebrovascular remodeling is observed, plectin and CD151 were strongly upregulated on all cerebral vessels, but surprisingly, in capillaries, this occurred in a β4 integrin-independent manner. Unexpectedly, absence of endothelial β4 integrin (in β4-EC-KO mice) had no impact on the expression level or distribution pattern of plectin and CD151 within stable or remodeling cerebral vessels. Conclusions: These results demonstrate that the HD proteins plectin and CD151 are closely associated with β4 integrin on arterioles in normal brain, and are strongly upregulated on remodeling blood vessels. However, unlike its described role in the epidermis, β4 integrin is not essential for localization or regulation of expression of plectin and CD151 in cerebral vessels