PERSPECTIVE Changing Face of Microglia Manuel B. Graeber Microglia are resident brain cells that sense pathological tissue alterations. They can develop into brain macrophages and perform immunological functions. However, expression of immune proteins by microglia is not synonymous with inflammation, because these molecules can have central nervous system (CNS)–specific roles. Through their involvement in pain mechanisms, microglia also respond to external threats. Experimental studies support the idea that microglia have a role in the maintenance of synaptic integrity. Analogous to electricians, they are capable of removing defunct axon terminals, thereby helping neuronal connections to stay intact. Microglia in healthy CNS tissue do not qualify as macrophages, and their specific functions are beginning to be explored. M icroglia are less numerous than neuro- glia but about as common as nerve cells. However, until 1991, a leading textbook of neuropathology stated (at the beginning of its chapter on microglia) that “... the microglia have become the most controversial element of the central nervous system; indeed, their very ex- istence is in doubt,” and the chapter concluded, “... the term ‘microglia,’ which implies a single dis- tinct cell system, is misleading and no longer ap- plicable” (1). Less than 20 years and more than 11,000 publications later, the microglia field has developed into a very active branch of neuroscience. Microglial cells have an extremely plastic, chameleon-like phenotype (Fig. 1). This was dem- onstrated conclusively with the advent of lectin and antibody markers, which label all microglial activation stages and their successful application in experimental models such as the facial nucleus axotomy paradigm. As a result, the historical con- troversy surrounding the “nature and identity” of microglial cells that had lasted for decades was resolved, and the microglial cell type became firm- ly established. Before special stains were avail- able, anatomists would see ramified microglia but could see “amoeboid” (macrophagelike) microglia only during central nervous system (CNS) devel- opment, whereas pathologists would encounter brain macrophages in different types of CNS le- sions but rarely make the connection to ramified microglia as the source. The recent debate about seemingly contradictory neurotrophic and neuro- toxic properties of microglia has to be viewed against the backdrop of microglial plasticity. Op- posite biological effects of one and the same cell type are well established for macrophages (2). Although the activity of microglia in immu- nological disease states (such as multiple sclero- sis) and in the removal of myelin debris is in line with their pathological role as macrophages and antigen-presenting cells, the discovery of microg- lial involvement in neurogenesis, postlesional “synaptic stripping,” and neuropathic pain under- scores the existence of additional, functionally adapted microglial phenotypes. The present re- view attempts to highlight aspects of this emerging face of microglial cells. The Microglial Immune Network Senses Threats to the CNS In addition to their marked functional plasticity, microglial cells are characterized by a very low threshold of activation. They respond to even minor pathological challenges that affect the CNS (3), directly or indirectly. An early report on microg- lial activation detailed the detection of increased expression of complement receptors following a peripheral nerve lesion (4), demonstrating that a remote, sterile stimulus is a sufficient trigger for microglial activation. Microglial activation (5) occurs within minutes (6) but can be long-lasting. It is difficult to imagine any brain or spinal cord pathology without a microglial response. Based on this principle, an entirely new approach to cell type–specific nervous system imaging was de- veloped by Banati et al. (see Fig. 2). However, the activation of microglia is anything but an un- specific process. The wide range of microglial re- sponse patterns and the great malleability of the microglial phenotype appear to be the result of the cells’ ability to respond in a very graded manner to changes in their environment (Fig. 1) (7). The microglial immune network has to be un- derstood as a figurative system for catching or entrapping pathogens, because, in a strictly ana- tomical sense, microglial cells are not connected like neuroglia. Research has failed to demonstrate gap junctions between microglia in vivo at the ultrastructural level, although one study has sug- gested their existence under pathological condi- tions (8). In line with this anatomical constraint, the microglial response to lesions mirrors the lo- cation of an insult far more precisely than that of astrocytes, which, unlike microglia, establish a syncytial network. In other words, microglial cells are more individualistic and keep their distance from each other while covering their own surveil- lance territory. Because of this absence of direct intercellular coupling, microglial cell communica- tion may have to rely more on auto- or parakrine mechanisms, as well as on purine and glutamate gradients (9). The cell processes of normal microglia are mobile and scan their microenvironment, even in healthy state (10). Therefore, “resting” microglia are sessile, but they are not inactive cells (10). Consequently, the use of the term “resting mi- croglia” without further explanation should be dis- couraged. Motility (that is, migration) of microglial cells is not usually observed in healthy CNS tissue, and the available literature suggests that when mi- croglia become motile, considerable damage to CNS tissue has occurred, requiring structural and functional repair. In contrast, perivascular cells (11), which are resident in the Virchow-Robin spaces, can migrate and are constantly renewed from the bone marrow. Unlike most tissue mac- rophages, microglia have retained their prolifer- ative potential. Perivascular cells constitutively express several molecules required for antigen pre- sentation (11) and form an immunological blood- brain barrier. In contrast, microglia respond to threats to the CNS parenchyma proper and only express molecules such as major histocompatibility complex (MHC) antigens on demand. The expres- sion of MHC class II molecules in human neuro- degenerative diseases, which might be perceived as a nonspecific microglial reaction because it is so common, may in reality represent an im- portant and, therefore, conserved mechanism to protect brain tissue that is already at risk (12). This view is supported by the intriguing finding that a human-specific gene expressed in cortical microglia, SIGLEC11 (13), serves to mediate im- munosuppressive signals and inhibits the function of microglial pattern-recognition receptors (14). The underlying human-specific gene conversion event has been said to be related to the evolution of the genus Homo (13), in keeping with the uniquely human evolution of sialic acid biology (15). Acti- vation of the brain’s microglial cells during systemic disease can provide an explanation for the feeling of illness and associated sickness behavior (16). Activation of Microglia Can Be Painful The role of microglia in the initiation of neu- ropathic pain appears to be crucial (17, 18). Neu- ropathic pain that occurs after peripheral nerve injury depends on the hyperexcitability of neu- rons in the dorsal horn of the spinal cord (18). At least five paths seem to exist that can lead to microglial activation in neuropathic nociceptive states, and the relevant molecular pathways in- clude fractalkine, interferon-g, monocyte chemo- attractant protein–1, TLR4, and P2X4 as the main signaling mediator and/or receptor (17). In addition, microglial P2X7Rs and their downstream signaling pathways play a pivotal role in the in- duction of spinal long-term potentiation (LTP) and persistent pain induced by tetanic stimula- tion, which produces LTP of C-fiber–evoked field potentials in the spinal cord (19). Activation of SPECIAL SECTION Brain and Mind Research Institute, University of Sydney, Cam- perdown, NSW 2050, Australia. E-mail: manuel@graeber.net www.sciencemag.org SCIENCE VOL 330 5 NOVEMBER 2010 783 on May 12, 2016 http://science.sciencemag.org/ Downloaded from