Animal models for studying microglia: The first, the popular, and the new.
Sieger D,Peri F
Glia. 2013 Jan;61(1):3-9. doi: 10.1002/glia.22385. Epub 2012 Sep 17.
Microglia, the resident phagocytes of brain, have been intensively studied since their discovery in the 1920s. There is no doubt that the possibility of culturing microglia in vitro has advanced enormously our understanding of these cells. However, as we know today, that microglia react to even small changes in the brain, it is crucial to also study these cells by preserving as much as possible their natural environment. Nowadays, advances in imaging technologies and transgenic cell labeling methods allow the direct observation of cells at work. These in vivo approaches have already changed our view on microglia by showing that these cells are active even in the healthy adult brain. As today, there is upcoming evidence that microglia can directly influence neuronal activity, understanding their roles and, in particular, their interactions with neurons is of great importance. The aim of this review is to illustrate three animal models that are currently used for microglial research and to discuss their characteristics and advantages by presenting recent achievements in microglial research. In our view the availability of different systems for studying microglia will lead to a more comprehensive understanding of their functions. (c) 2012 Wiley Periodicals, Inc.
Long-Range Ca(2+) Waves Transmit Brain-Damage Signals to Microglia.
Sieger, D., Moritz, C., Ziegenhals, T., Prykhozhij, S. & Peri, F.
Dev Cell. 2012 May 23.
Microglia are the resident phagocytes of the brain that are responsible for the clearance of injured neurons, an essential step in subsequent tissue regeneration. How death signals are controlled both in space and time to attract these cells toward the site of injury is a topic of great interest. To this aim, we have used the optically transparent zebrafish larval brain and identified rapidly propagating Ca(2+) waves that determine the range of microglial responses to neuronal cell death. We show that while Ca(2+)-mediated microglial responses require ATP, the spreading of intercellular Ca(2+) waves is ATP independent. Finally, we identify glutamate as a potent inducer of Ca(2+)-transmitted microglial attraction. Thus, this real-time analysis reveals the existence of a mechanism controlling microglial targeted migration to neuronal injuries that is initiated by glutamate and proceeds across the brain in the form of a Ca(2+) wave. VIDEO ABSTRACT:
Microglia in the developing brain: from immunity to behaviour.
Schlegelmilch, T., Henke, K. & Peri, F.
Curr Opin Neurobiol. 2010 Sep 2.
For decades, microglia, the resident macrophages of the brain, have been recognized mostly for their role in several, if not all, pathologies affecting the brain. However, several studies under physiological conditions demonstrate that microglial function is indispensable also in the healthy brain. Indeed, microglia implement key functions already during development, such as the clearance of the huge amount of neurons that are produced in large excess in the embryo and later die of apoptosis. Beside these classical functions, however, novel roles are emerging that strikingly link microglia with higher order brain functions and show that these cells can ultimately influence behaviour. Therefore a detailed understanding of microglia under physiological conditions may open unprecedented perspectives in the prevention and treatment of neuropsychiatric diseases.
Breaking ranks: how leukocytes react to developmental cues and tissue injury.
Curr Opin Genet Dev. 2010 Aug;20(4):416-9. Epub 2010 Jun 2.
Leukocytes are arguably the most motile cells in metazoans. Besides their well-described ability to migrate rapidly toward sites of tissue injury, tissue-specific macrophages migrate already during embryogenesis, when they take up residence in a wide range of organs. The recent identification of molecules responsible for the guidance of leukocytes during development and in response to injury has revealed that these modes of migration are under the control of surprisingly different signaling systems. While the developmental migrations are regulated by hard-wired pre-patterns of secreted proteins, the rapid acute response to injury involves signals like hydrogen peroxide or extracellular nucleotides such as ATP. Ongoing work aims to understand how these distinct signals are integrated in the cell to determine different cellular responses.
Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction.
Fantin, A., Vieira, J.M., Gestri, G., Denti, L., Schwarz, Q., Prykhozhij, S., Peri, F., Wilson, S.W. & Ruhrberg, C.
Blood. 2010 Apr 19.
Blood vessel networks expand in a two-step process that begins with vessel sprouting and is followed by vessel anastomosis. Vessel sprouting is induced by chemotactic gradients of the vascular endothelial growth factor VEGF, which stimulates tip cell protrusion. Yet, it is not known which factors promote the fusion of neighbouring tip cells to add new circuits to the existing vessel network. By combining the analysis of mouse mutants defective in macrophage development or VEGF signalling with live imaging in zebrafish, we now show that macrophages promote tip cell fusion downstream of VEGF-mediated tip cell induction. Macrophages therefore play a hitherto unidentified and unexpected role as vascular fusion cells. Moreover, we show that there are striking molecular similarities between the pro-angiogenic tissue macrophages essential for vascular development and those that promote the angiogenic switch in cancer, including the expression of the cell surface proteins TIE2 and NRP1. Our findings suggest that tissue macrophages are a target for anti-angiogenic therapies, but that they could equally well be exploited to stimulate tissue vascularisation in ischemic disease.
Live imaging of neuronal degradation by microglia reveals a role for v0-ATPase a1 in phagosomal fusion in vivo.
Peri, F. & Nusslein-Volhard, C.
Cell. 2008 May 30;133(5):916-27.
A significant proportion of neurons in the brain undergo programmed cell death. In order to prevent the diffusion of damaging degradation products, dying neurons are quickly digested by microglia. Despite the importance of microglia in several neuronal pathologies, the mechanism underlying their degradation of neurons remains elusive. Here, we exploit a microglial population in the zebrafish to study this process in intact living brains. In vivo imaging reveals that digestion of neurons occurs in compartments arising from the progressive fusion of vesicles. We demonstrate that this fusion is mediated by the v0-ATPase a1 subunit. By applying live pH indicators, we show that the a1 subunit mediates fusion between phagosomes and lysosomes during phagocytosis, a function that is independent of its proton pump activity. As a real-time description of microglial phagocytosis in vivo, this work advances our understanding of microglial-mediated neuronal degeneration, a hallmark of many neuronal diseases.
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