Butovsky, O., Talpalar, A. E., Ben-Yaakov, K. & Schwartz, M. Activation of microglia by aggregated -amyloid or lipopolysaccharide impairs MHC-II expression and renders them cytotoxic whereas IFN- and IL-4 render them protective. Mol. Cell. Neurosci. 29, 381-393

Department of Neurobiology, The Weizmann Institute of Science, 76100 Rehovot, Israel.
Molecular and Cellular Neuroscience (Impact Factor: 3.84). 08/2005; 29(3):381-93. DOI: 10.1016/j.mcn.2005.03.005
Source: PubMed


'Protective autoimmunity' refers to a well-controlled anti-self response that helps the body resist neurodegeneration. The response is mediated by autoimmune T cells, which produce cytokines and growth factors. Using an in vitro assay of hippocampal slices, we show that the cytokines interferon-gamma and (especially) interleukin-4, characteristic of pro-inflammatory and anti-inflammatory T cells, respectively, can make microglia neuroprotective. Aggregated beta-amyloid, like bacterial cell wall-derived lipopolysaccharide, rendered the microglia cytotoxic. Cytotoxicity was correlated with a signal transduction pathway that down-regulates expression of class-II major histocompatibility proteins (MHC-II) through the MHC-II-transactivator and the invariant chain. Protection by interleukin-4 was attributed to down-regulation of tumor necrosis factor-alpha and up-regulation of insulin-like growth factor I. These findings suggest that beneficial or harmful expression of the local immune response in the damaged CNS depends on how microglia interpret the threat, and that a well-regulated T-cell-mediated response enables microglia to alleviate rather than exacerbate stressful situations in the CNS.

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Available from: Adolfo Talpalar, Mar 05, 2015
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    • "All this evidence supports our findings and suggests that the consumption of an HCD triggers a reactive astrogliosis in the temporal cortex and hippocampus of the rat. Previous studies indicate that persistent activation of glia promotes increased concentration of proinflammatory agents as the cytokine release prior to neuronal death (Butovsky et al., 2005; Eiklenboom and van Gool, 2004: Veerhuis et al., 2005). Cytokines are considered to be regulators of the intensity and duration of the inflammatory process (Tuppo and Arias, 2005), because they stimulate activation of various signaling pathways in response to cellular stress, leading to the development of oxidative stress and neuronal death (Hardy and Selkoe, 2002; Minagar et al., 2002). "
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    ABSTRACT: A high calorie intake can induce the appearance of the metabolic syndrome (MS), which is a serious public health problem because it affects glucose levels and triglycerides in the blood. Recently, it has been suggested that MS can cause complications in the brain, since chronic hyperglycemia and insulin resistance are risk factors for triggering neuronal death by inducing a state of oxidative stress and inflammatory response that affect cognitive processes. This process, however, is not clear. In this study, we evaluated the effect of the consumption of a high-calorie diet (HCD) on both neurodegeneration and spatial memory impairment in rats. Our results demonstrated that HCD (90 day consumption) induces an alteration of the main energy metabolism markers, indicating the development of MS in rats. Moreover, an impairment of spatial memory was observed. Subsequently, the brains of these animals showed activation of an inflammatory response (increase in reactive astrocytes and interleukin1-β as well as tumor necrosis factor-α) and oxidative stress (reactive oxygen species and lipid peroxidation), causing a reduction in the number of neurons in the temporal cortex and hippocampus. Altogether, these results suggest that a HCD promotes the development of MS and contributes to the development of a neurodegenerative process and cognitive failure. In this regard, it is important to understand the relationship between MS and neuronal damage in order to prevent the onset of neurodegenerative disorders. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
    Synapse 06/2015; 69(9). DOI:10.1002/syn.21832 · 2.13 Impact Factor
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    • "Polarization toward classic activation (M1) can be induced experimentally by exposure to pro-inflammatory cytokines such as interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha and interleukin (Il)-1beta, as well as bacterial-derived LPS (Lehnardt et al., 2003). Alternative M2 (protective) activation of microglia is characterized by increased expression of the anti-inflammatory cytokines Il-4, Il-10, and transforming growth factor (TGF)-beta, CD200, and growth factors such as insulin growth factor (IGF)-1, nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF; Butovsky et al., 2005; Yi et al., 2012). Alternative activation can be induced experimentally by anti-inflammatory cytokines such as Il-4 and Il-13 (Butovsky et al., 2006; Colton, 2009). "
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    ABSTRACT: Throughout life new neurons are continuously added to the hippocampal circuitry involved with spatial learning and memory. These new cells originate from neural precursors in the subgranular zone of the dentate gyrus, migrate into the granule cell layer, and integrate into neural networks encoding spatial and contextual information. This process can be influenced by several environmental and endogenous factors and is modified in different animal models of neurological disorders. Neuroinflammation, as defined by the presence of activated microglia, is a common key factor to the progression of neurological disorders. Analysis of the literature shows that microglial activation impacts not only the production, but also the migration and the recruitment of new neurons. The impact of microglia on adult-born neurons appears much more multifaceted than ever envisioned before, combining both supportive and detrimental effects that are dependent upon the activation phenotype and the factors being released. The development of strategies aimed to change microglia toward states that promote functional neurogenesis could therefore offer novel therapeutic opportunities against neurological disorders associated with cognitive deficits and neuroinflammation. The present review summarizes the current knowledge on how production, distribution, and recruitment of new neurons into behaviorally relevant neural networks are modified in the inflamed hippocampus.
    Frontiers in Cellular Neuroscience 09/2013; 7:145. DOI:10.3389/fncel.2013.00145 · 4.29 Impact Factor
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    • "In addition, treatment of NSCs with IL-4 also lead to a greater degree of chemotaxis of these cells to RANTES (regulated on activation, normal T cell expressed and secreted) (Guan et al., 2008). As mentioned above, microglia modulated by IL-4 encourage adult neurogenesis and provide neuroprotection in vitro (Butovsky et al., 2005). Adult NSCs engineered to express IL-10 show a greater ability to induce immune suppression, remyelination, and neuronal repair, thereby possibly outlining a novel approach to improve the efficacy of NSC-based therapy in CNS disease (Yang et al., 2009). "
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    ABSTRACT: The pharmacological support and stimulation of endogenous and transplanted neural stem cells (NSCs) is a major challenge in brain repair. Trauma to the central nervous system (CNS) results in a distinct inflammatory response caused by local and infiltrating immune cells. This makes NSC-supported regeneration difficult due to the presence of inhibitory immune factors which are upregulated around the lesion site. The continual and dual role of the neuroinflammatory response leaves it difficult to decipher upon a single modulatory strategy. Therefore, understanding the influence of cytokines upon regulation of NSC self-renewal, proliferation and differentiation is crucial when designing therapies for CNS repair. There is a plethora of partially conflicting data in vitro and in vivo on the role of cytokines in modulating the stem cell niche and the milieu around NSC transplants. This is mainly due to the pleiotropic role of many factors. In order for cell-based therapy to thrive, treatment must be phase-specific to the injury and also be personalized for each patient, i.e. taking age, sex, neuroimmune and endocrine status as well as other key parameters into consideration. In this review, we will summarize the most relevant information concerning interleukin (IL)-1, IL-4, IL-10, IL-15, IFN-γ, the neuropoietic cytokine family and TNF-α in order to extract promising therapeutic approaches for further research. We will focus on the consequences of neuroinflammation on endogenous brain stem cells and the transplantation environment, the effects of the above cytokines on NSCs, as well as immunopharmacological manipulation of the microenvironment for potential therapeutic use.
    Pharmacology [?] Therapeutics 08/2013; 141(1). DOI:10.1016/j.pharmthera.2013.08.001 · 9.72 Impact Factor
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