Microglial physiology: unique stimuli, specialized responses

doi:10.1146/ANNUREV.IMMUNOL.021908.132528

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Microglial physiology: unique stimuli, specialized responses

Journal Article•DOI•

Microglial physiology: unique stimuli, specialized responses

Richard M. Ransohoff¹, V. Hugh Perry²•Institutions (2)

Cleveland Clinic Lerner Research Institute¹, University of Southampton²

20 Mar 2009-Annual Review of Immunology (Annual Reviews)-Vol. 27, Iss: 1, pp 119-145

TL;DR: A wealth of data now demonstrate that the microglia have very diverse effector functions, in line with macrophage populations in other organs, and the term activatedmicroglia needs to be qualified to reflect the distinct and very different states of activation-associated effector function in different disease states.

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Abstract: Microglia, the macrophages of the central nervous system parenchyma, have in the normal healthy brain a distinct phenotype induced by molecules expressed on or secreted by adjacent neurons and astrocytes, and this phenotype is maintained in part by virtue of the blood-brain barrier's exclusion of serum components. Microglia are continually active, their processes palpating and surveying their local microenvironment. The microglia rapidly change their phenotype in response to any disturbance of nervous system homeostasis and are commonly referred to as activated on the basis of the changes in their morphology or expression of cell surface antigens. A wealth of data now demonstrate that the microglia have very diverse effector functions, in line with macrophage populations in other organs. The term activated microglia needs to be qualified to reflect the distinct and very different states of activation-associated effector functions in different disease states. Manipulating the effector functions of microglia has the potential to modify the outcome of diverse neurological diseases.

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Journal Article•DOI•

Fate Mapping Analysis Reveals That Adult Microglia Derive from Primitive Macrophages

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Florent Ginhoux¹, Florent Ginhoux², Melanie Greter¹, Marylene Leboeuf¹, Sayan Nandi³, Peter See², Solen Gokhan³, Mark F. Mehler³, Simon J. Conway⁴, Lai Guan Ng², E. Richard Stanley³, Igor M. Samokhvalov, Miriam Merad¹ - Show less +9 more•Institutions (4)

Icahn School of Medicine at Mount Sinai¹, Singapore Immunology Network², Albert Einstein College of Medicine³, Indiana University⁴

05 Nov 2010-Science

TL;DR: Results identify microglia as an ontogenically distinct population in the mononuclear phagocyte system and have implications for the use of embryonically derived microglial progenitors for the treatment of various brain disorders.

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Abstract: Microglia are the resident macrophages of the central nervous system and are associated with the pathogenesis of many neurodegenerative and brain inflammatory diseases; however, the origin of adult microglia remains controversial. We show that postnatal hematopoietic progenitors do not significantly contribute to microglia homeostasis in the adult brain. In contrast to many macrophage populations, we show that microglia develop in mice that lack colony stimulating factor-1 (CSF-1) but are absent in CSF-1 receptor-deficient mice. In vivo lineage tracing studies established that adult microglia derive from primitive myeloid progenitors that arise before embryonic day 8. These results identify microglia as an ontogenically distinct population in the mononuclear phagocyte system and have implications for the use of embryonically derived microglial progenitors for the treatment of various brain disorders.

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3,894 citations

Journal Article•DOI•

Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner.

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Dorothy P. Schafer¹, Emily K. Lehrman¹, Amanda G. Kautzman¹, Ryuta Koyama¹, Alan R. Mardinly¹, Ryo Yamasaki², Richard M. Ransohoff², Michael E. Greenberg¹, Ben A. Barres³, Beth Stevens¹ - Show less +6 more•Institutions (3)

Harvard University¹, Cleveland Clinic Lerner Research Institute², Stanford University³

24 May 2012-Neuron

TL;DR: It is shown that microglia engulf presynaptic inputs during peak retinogeniculate pruning and that engulfment is dependent upon neural activity and themicroglia-specific phagocytic signaling pathway, complement receptor 3(CR3)/C3.

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2,864 citations

Cites background from "Microglial physiology: unique stimu..."

...…work has demonstrated that microglia have the capacity to interact with synaptic elements in response to neurotransmitter release and/or sensory experience (Biber et al., 2007; Fontainhas et al., 2011; Nimmerjahn et al., 2005; Ransohoff and Perry, 2009; Tremblay et al., 2010a; Wake et al., 2009)....
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...Microglia are the resident CNS immune cells which have long been recognized as rapid responders to injury and disease, playing a role in a broad range of processes such as tissue inflammation and clearance of cellular debris (Hanisch and Kettenmann, 2007; Kreutzberg, 1996; Ransohoff and Perry, 2009)....
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...Interestingly, early postnatal microglia also had processes, a morphological characteristic of ‘resting’ microglia which are resident in the healthy adult brain (Figure S2B; Lynch, 2009; Ransohoff and Perry, 2009)....
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...Engulfment of RGC Inputs by Microglia Is an Activity-Dependent Process Previous work has demonstrated that microglia have the capacity to interact with synaptic elements in response to neurotransmitter release and/or sensory experience (Biber et al., 2007; Fontainhas et al., 2011; Nimmerjahn et al., 2005; Ransohoff and Perry, 2009; Tremblay et al., 2010a; Wake et al., 2009)....
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...Particularly during CNS disease, microglia are known scavengers that phagocytose cellular debris (Hanisch and Kettenmann, 2007; Napoli and Neumann, 2009; Ransohoff and Perry, 2009)....
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Journal Article•DOI•

Host microbiota constantly control maturation and function of microglia in the CNS

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Daniel Erny¹, Anna Lena Hrabě de Angelis¹, Diego Jaitin², Peter Wieghofer¹, Ori Staszewski¹, Eyal David², Hadas Keren-Shaul², Tanel Mahlakõiv¹, Kristin Jakobshagen³, Thorsten Buch⁴, Vera Schwierzeck⁵, Olaf Utermöhlen³, Eunyoung Chun⁶, Wendy S. Garrett⁶, Kathy D. McCoy⁷, Andreas Diefenbach⁵, Peter Staeheli¹, Bärbel Stecher⁸, Ido Amit², Marco Prinz¹ - Show less +16 more•Institutions (8)

University of Freiburg¹, Weizmann Institute of Science², University of Cologne³, Technische Universität München⁴, University of Mainz⁵, Harvard University⁶, University of Bern⁷, Ludwig Maximilian University of Munich⁸

01 Jul 2015-Nature Neuroscience

TL;DR: It is determined that short-chain fatty acids (SCFA), microbiota-derived bacterial fermentation products, regulated microglia homeostasis and mice deficient for the SCFA receptor FFAR2 mirroredmicroglia defects found under GF conditions, suggesting that host bacteria vitally regulate microglian maturation and function.

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Abstract: As the tissue macrophages of the CNS, microglia are critically involved in diseases of the CNS. However, it remains unknown what controls their maturation and activation under homeostatic conditions. We observed substantial contributions of the host microbiota to microglia homeostasis, as germ-free (GF) mice displayed global defects in microglia with altered cell proportions and an immature phenotype, leading to impaired innate immune responses. Temporal eradication of host microbiota severely changed microglia properties. Limited microbiota complexity also resulted in defective microglia. In contrast, recolonization with a complex microbiota partially restored microglia features. We determined that short-chain fatty acids (SCFA), microbiota-derived bacterial fermentation products, regulated microglia homeostasis. Accordingly, mice deficient for the SCFA receptor FFAR2 mirrored microglia defects found under GF conditions. These findings suggest that host bacteria vitally regulate microglia maturation and function, whereas microglia impairment can be rectified to some extent by complex microbiota.

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2,096 citations

Journal Article•DOI•

Obesity is associated with hypothalamic injury in rodents and humans

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Joshua P. Thaler¹, Chun-Xia Yi², Ellen A. Schur¹, Stephan J. Guyenet¹, Bang H. Hwang, Marcelo O. Dietrich³, Xiaolin Zhao⁴, David A. Sarruf⁵, Vitaly Izgur¹, Kenneth R. Maravilla¹, Hong T. Nguyen¹, Jonathan D. Fischer¹, Miles E. Matsen¹, Brent E. Wisse¹, Gregory J. Morton¹, Tamas L. Horvath³, Denis G. Baskin, Matthias H. Tschöp², Michael W. Schwartz¹ - Show less +15 more•Institutions (5)

University of Washington¹, University of Cincinnati², Yale University³, Xi'an Jiaotong University⁴, Novo Nordisk⁵

03 Jan 2012-Journal of Clinical Investigation

TL;DR: Obesity is associated with neuronal injury in a brain area crucial for body weight control in both humans and rodent models, and evidence of increased gliosis in the mediobasal hypothalamus of obese humans is found.

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Abstract: Rodent models of obesity induced by consuming high-fat diet (HFD) are characterized by inflammation both in peripheral tissues and in hypothalamic areas critical for energy homeostasis. Here we report that unlike inflammation in peripheral tissues, which develops as a consequence of obesity, hypothalamic inflammatory signaling was evident in both rats and mice within 1 to 3 days of HFD onset, prior to substantial weight gain. Furthermore, both reactive gliosis and markers suggestive of neuron injury were evident in the hypothalamic arcuate nucleus of rats and mice within the first week of HFD feeding. Although these responses temporarily subsided, suggesting that neuroprotective mechanisms may initially limit the damage, with continued HFD feeding, inflammation and gliosis returned permanently to the mediobasal hypothalamus. Consistent with these data in rodents, we found evidence of increased gliosis in the mediobasal hypothalamus of obese humans, as assessed by MRI. These findings collectively suggest that, in both humans and rodent models, obesity is associated with neuronal injury in a brain area crucial for body weight control.

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1,432 citations

Journal Article•DOI•

Amyloid Oligomers Exacerbate Tau Pathology in a Mouse Model of Tauopathy

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Maj Linda B. Selenica¹, Milene Brownlow¹, Jeffy Jimenez¹, Daniel C. Lee¹, Gabriela Pena¹, Chad A. Dickey¹, Marcia N. Gordon¹, Dave Morgan¹ - Show less +4 more•Institutions (1)

University of South Florida¹

11 Apr 2013-Neurodegenerative Diseases

TL;DR: The data suggest that even brief elevations in Aβ production, may have enduring impact on the risk for tauopathy, and Soluble Aβ1-42 oligomers have long-lasting effects on tau phosphorylation in the rTg4510 model.

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Abstract: Background: We aimed to investigate the influence of oligomeric forms of β-amyloid (Aβ) and the influence of the duration of exposure on the development of tau ph

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1,423 citations

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References

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Journal Article•DOI•

Alternative activation of macrophages

[...]

Siamon Gordon¹•Institutions (1)

University of Oxford¹

01 Jan 2003-Nature Reviews Immunology

TL;DR: The evidence in favour of alternative macrophage activation by the TH2-type cytokines interleukin-4 (IL-4) and IL-13 is assessed, and its limits and relevance to a range of immune and inflammatory conditions are defined.

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Abstract: The classical pathway of interferon-gamma-dependent activation of macrophages by T helper 1 (T(H)1)-type responses is a well-established feature of cellular immunity to infection with intracellular pathogens, such as Mycobacterium tuberculosis and HIV. The concept of an alternative pathway of macrophage activation by the T(H)2-type cytokines interleukin-4 (IL-4) and IL-13 has gained credence in the past decade, to account for a distinctive macrophage phenotype that is consistent with a different role in humoral immunity and repair. In this review, I assess the evidence in favour of alternative macrophage activation in the light of macrophage heterogeneity, and define its limits and relevance to a range of immune and inflammatory conditions.

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5,930 citations

"Microglial physiology: unique stimu..." refers background in this paper

...The response of the microglia is not a linear process varying simply by degree, but rather, as has been documented in other macrophage populations, their response is dictated by the nature of the stimulus, the receptor repertoire that is engaged, and the prior state of the macrophage (97) (see section on Defining Microglial Activation)....
[...]

Journal Article•DOI•

Monocyte and macrophage heterogeneity

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Siamon Gordon¹, Philip R. Taylor¹•Institutions (1)

University of Oxford¹

01 Dec 2005-Nature Reviews Immunology

TL;DR: Recent studies have shown that monocyte heterogeneity is conserved in humans and mice, allowing dissection of its functional relevance: the different monocyte subsets seem to reflect developmental stages with distinct physiological roles, such as recruitment to inflammatory lesions or entry to normal tissues.

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Abstract: Heterogeneity of the macrophage lineage has long been recognized and, in part, is a result of the specialization of tissue macrophages in particular microenvironments. Circulating monocytes give rise to mature macrophages and are also heterogeneous themselves, although the physiological relevance of this is not completely understood. However, as we discuss here, recent studies have shown that monocyte heterogeneity is conserved in humans and mice, allowing dissection of its functional relevance: the different monocyte subsets seem to reflect developmental stages with distinct physiological roles, such as recruitment to inflammatory lesions or entry to normal tissues. These advances in our understanding have implications for the development of therapeutic strategies that are targeted to modify particular subpopulations of monocytes.

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4,861 citations

"Microglial physiology: unique stimu..." refers background in this paper

...Although the two monocyte populations are believed to originate from a bone marrow progenitor by cell-autonomous mechanisms, differential properties of tissue macrophages probably derive mainly from environmental cues (54)....
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Journal Article•DOI•

Resting Microglial Cells Are Highly Dynamic Surveillants of Brain Parenchyma in Vivo

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Axel Nimmerjahn¹, Frank Kirchhoff¹, Fritjof Helmchen¹•Institutions (1)

Max Planck Society¹

27 May 2005-Science

TL;DR: Using in vivo two-photon imaging in neocortex, it is found that microglial cells are highly active in their presumed resting state, continually surveying their microenvironment with extremely motile processes and protrusions.

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Abstract: Microglial cells represent the immune system of the mammalian brain and therefore are critically involved in various injuries and diseases. Little is known about their role in the healthy brain and their immediate reaction to brain damage. By using in vivo two-photon imaging in neocortex, we found that microglial cells are highly active in their presumed resting state, continually surveying their microenvironment with extremely motile processes and protrusions. Furthermore, blood-brain barrier disruption provoked immediate and focal activation of microglia, switching their behavior from patroling to shielding of the injured site. Microglia thus are busy and vigilant housekeepers in the adult brain.

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4,458 citations

"Microglial physiology: unique stimu..." refers background in this paper

...Despite the downregulated phenotype of microglia in the normal healthy brain, in vivo imaging studies demonstrate that the fine processes of microglia continually palpate and monitor their local microenvironment (5, 6)....
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...Both groups made the same surprising observation: that microglia in the intact, healthy CNS continually remodel their processes, in apparent surveillance of the extracellular milieu (5, 6)....
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Journal Article•DOI•

Microglia: a sensor for pathological events in the CNS

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Georg W. Kreutzberg¹•Institutions (1)

Max Planck Society¹

01 Aug 1996-Trends in Neurosciences

TL;DR: An understanding of intercellular signalling pathways for microglia proliferation and activation could form a rational basis for targeted intervention on glial reactions to injuries in the CNS.

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4,372 citations

"Microglial physiology: unique stimu..." refers background in this paper

...Microglia are exquisitely sensitive to disturbances of their microenvironment, and they have been dubbed the sensors of pathology (96)....
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Journal Article•DOI•

Inflammation and Alzheimer's disease.

[...]

Haruhiko Akiyama, Steven W. Barger, Scott R. Barnum, B Bradt, Jürgen Bauer, Greg M. Cole, Neil R. Cooper, Piet Eikelenboom, Mark R. Emmerling, Bernd L. Fiebich, Caleb E. Finch, Sally A. Frautschy, W. S. T. Griffin, Harald Hampel, Michael Hüll, Gary E. Landreth, Lih-Fen Lue, Robert E. Mrak, Ian R. A. Mackenzie, Patrick L. McGeer, M K O'Banion, Joel S. Pachter, Giulio Maria Pasinetti, C Plata-Salaman, Joseph G. Rogers, Russell E. Rydel, Yueyang Shen, Wolfgang J. Streit, Ronald Strohmeyer, I Tooyoma, F L van Muiswinkel, R. Veerhuis, David G. Walker, Scott D. Webster, Beatrice Hauss–Wegrzyniak, Gary L. Wenk, Tony Wyss-Coray - Show less +33 more

01 May 2000-Neurobiology of Aging

TL;DR: By better understanding AD inflammatory and immunoregulatory processes, it should be possible to develop anti-inflammatory approaches that may not cure AD but will likely help slow the progression or delay the onset of this devastating disorder.

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4,319 citations

"Microglial physiology: unique stimu..." refers background in this paper

...The role of inflammation in AD has been extensively researched and exhaustively reviewed (103, 104), but the contributions to the disease of the microglia and the associated innate inflammatory response are by no means clear....
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