Please review trhe following:

Microglia, macrophages, perivascular macrophages, and pericytes: a review of function and identification. March 2004 Journal of Leukocyte Biology vol. 75 no. 3 388-397                                    

Gilles J. Guillemin*,†,1 and Bruce J. Brew‡

Abstract

The phenotypic differentiation of systemic macrophages that have infiltrated the central nervous system, pericytes, perivascular macrophages, and the “real” resident microglial cells is a major immunocytochemical and immunohistochemical concern for all users of cultures of brain cells and brain sections. It is not only important in assessing the purity of cell cultures; it is also of fundamental importance in the assessment of the pathogenetic significance of perivascular inflammatory phenomena within the brain. The lack of a single membranous and/or biochemical marker allowing conclusive identification of these cells is still a major problem in neurobiology. This review briefly discusses the functions of these cells and catalogs a large number of membranous and biochemical markers, which can assist in the identification of these cells.

The role of microglia and macrophages in the pathophysiology of the CNS

Progress in Neurobiology Volume 58, Issue 3, June 1999, Pages 233–247

Guido Stollg, Sebastian Jander

Abstract

Microglia are a major glial component of the central nervous system (CNS) and are extremely sessile. Only a subtype, the perivascular microglia, are regularly replaced from the bone marrow in adult animals. Microglia respond to virtually any, even minor pathological events in the CNS. In most pathological settings microglia are aided by infiltrating hematogenous macrophages.

Upon activation microglia and macrophages share most phenotypical markers and can exert similar effector functions. After transection of a CNS fibre tract microglia are insufficiently activated and hematogenous macrophages do not significantly enter the degenerating nerve stump. Thereby myelin debris that contains neurite outgrowth inhibiting activity persists for long time. This is in sharp contrast to the peripheral nervous system in which hematogenous macrophages are rapidly recruited in response to axotomy and clear myelin debris allowing regrowth of axons from the proximal stump.

However, CNS lesion paradigms with breakdown of the blood–brain barrier such as cerebral ischemia, brain abscesses and stab wounds elicit prompt microglial activation, macrophage recruitment and debris clearance.

There is increasing evidence that microglia play an active part in degenerative CNS diseases. In Alzheimer’s disease activated microglia appear to be involved in plaque formation. In experimental globoid cell dystrophy T-cell independent induction of major histocompatibility complex class II molecules on microglia accelerates demyelination.

In autoimmune diseases microglia probably have dual functions.

Microglia present antigen to infiltrating T cells and exert effector functions thereby locally augmenting immune responses. On the other hand, microglia have the capacity to downregulate T cell responses. In the human acquired immunodeficiency syndrome (AIDS) virus infected macrophages probably introduce the virus to the CNS and in concert with microglia are involved in the pathophysiology of the AIDS dementia

J Neuroinflammation. 2014 Dec 31;11(1):1031. [Epub ahead of print]

Heterogeneous induction of microglia M2a phenotype by central administration of

interleukin-4.

Pepe G, Calderazzi G, De Maglie M, Villa A, Vegeto E.

BackgroundAcquisition of the M1 or M2 phenotypes by microglia has been shown to

occur during the development of pathological conditions, with M1 activation being

widely involved in neurotoxicity in relation with the anatomical localization and

the reactivity of subtypes of microglia cells. On the contrary, little is known

on the ability of microglia to undergo M2 polarization by interleukin-4 (IL4),

the typical M2a polarization signal for peripheral macrophages.MethodsRecombinant

mouse IL4 was injected in the third cerebral ventricle of mice to induce brain

alternative polarization. The mRNA levels of Fizz1, Arg1, and Ym1 genes, known to

be up-regulated by IL4 in peripheral macrophages, together with additional

polarization markers, were evaluated in the striatum and frontal cortex at

different time intervals after central administration of IL4; in parallel, M2a

protein expression was evaluated in tissue extracts and at the cellular

level.ResultsOur results show that the potency and temporal profile of

IL4-mediated M2a gene induction vary depending on the gene analyzed and according

to the specific brain area analyzed, with the striatum showing a reduced M2a

response compared with the frontal cortex, as further substantiated by assays of

polarization protein levels. Of notice, Fizz1 mRNA induction reached 100-fold

level, underscoring the potency of this specific IL4 signaling pathway in the

brain. In addition, immunochemistry assays demonstrated the localization of the

M2 response specifically to microglia cells and, more interestingly, the

existence of a subpopulation of microglia cells amenable to undergoing M2a

polarization in the healthy mouse brain.ConclusionsThese results show that the

responsiveness of brain macrophages to centrally administered IL4 may vary

depending on the gene and brain area analyzed, and that M2a polarization can be

ascribed to a subpopulation of IL4-responsive microglia cells. The biochemical

pathways that enable microglia to undergo M2a activation represent key aspects

for understanding the physiopathology of neuroinflammation and for developing

novel therapeutic and diagnostic agents.

PMCID: PMC4302702

PMID: 25551794  [PubMed - as supplied by publisher]

2. Int J Cancer. 2014 Dec 5. doi: 10.1002/ijc.29379. [Epub ahead of print]

Resident microglia, and not peripheral macrophages, are the main source of brain

tumor mononuclear cells.

Müller A(1), Brandenburg S, Turkowski K, Müller S, Vajkoczy P.

Author information:

(1)Department of Neurosurgery, Charité-Universitätsmedizin Berlin, Berlin,

Germany.

Gliomas consist of multiple cell types, including an abundant number of microglia

and macrophages, whereby their impact on tumor progression is controversially

discussed. To understand their unique functions and consequently manipulate

either microglia or macrophages in therapeutic approaches, it is essential to

discriminate between both cell populations. Because of the lack of specific

markers, generally total body irradiated chimeras with labeled bone marrow cells

were used to identify infiltrated cells within the brain. However, total body

irradiation (TBI) affects the blood-brain barrier integrity, which in turn

potentially facilitates immune cell infiltration. In this study, changes on the

blood-brain barrier were avoided using head-protected irradiation (HPI). Head

protection and total body irradiated chimeras exhibited similar reconstitution

levels of the myeloid cell lineage in the blood, enabling the comparable analyses

of brain infiltrates. We demonstrate that the HPI model impeded a massive

unspecific influx of donor-derived myeloid cells into naive as well as

tumor-bearing brains. Moreover, experimental artifacts such as an enlarged

distribution of infiltrated cells and fourfold increased tumor volumes are

prevented in head-protected chimeras. In addition, our data evidenced for the

first time that microglia are able to up-regulate CD45 and represent an inherent

part of the CD45(high) population in the tumor context. All in all, HPI allowed

for the unequivocal distinction between microglia and macrophages without

alterations of tumor biology and consequently permits a detailed and realistic

description of the myeloid cell composition in gliomas.

© 2014 UICC.

PMID: 25477239  [PubMed - as supplied by publisher]

3. J Neurosci Res. 2015 Apr;93(4):549-61. doi: 10.1002/jnr.23513. Epub 2014 Nov 19.

A rodent model of mild traumatic brain blast injury.

Perez-Polo JR(1), Rea HC, Johnson KM, Parsley MA, Unabia GC, Xu GY, Prough D,

DeWitt DS, Spratt H, Hulsebosch CE.

Author information:

(1)University of Texas Medical Branch, Galveston, Texas.

One of the criteria defining mild traumatic brain injury (mTBI) in humans is a

loss of consciousness lasting for less than 30 min. mTBI can result in long-term

impairment of cognition and behavior. In rats, the length of time it takes a rat

to right itself after injury is considered to be an analog for human return to

consciousness. This study characterized a rat mild brain blast injury (mBBI)

model defined by a righting response reflex time (RRRT) of more than 4 min but

less than 10 min. Assessments of motor coordination relying on beam-balance and

foot-fault assays and reference memory showed significant impairment in animals

exposed to mBBI. This study's hypothesis is that there are inflammatory outcomes

to mTBI over time that cause its deleterious effects. For example, mBBI

significantly increased brain levels of interleukin (IL)-1β and tumor necrosis

factor-α (TNFα) protein. There were significant inflammatory responses in the

cortex, hippocampus, thalamus, and amygdala 6 hr after mBBI, as evidenced by

increased levels of the inflammatory markers associated with activation of

microglia and macrophages, ionized calcium binding adaptor 1 (IBA1), impairment

of the blood-brain barrier, and significant neuronal losses. There were

significant increases in phosphorylated Tau (p-Tau) levels, a putative precursor

to the development of neuroencephalopathy, as early as 6 hr after mBBI in the

cortex and the hippocampus but not in the thalamus or the amygdala. There was an

apparent correlation between RRRTs and p-Tau protein levels but not IBA1. These

results suggest potential therapies for mild blast injuries via blockade of the

IL-1β and TNFα receptors.

© 2014 Wiley Periodicals, Inc.

PMID: 25410497  [PubMed - in process]

4. BMC Infect Dis. 2014 Jul 11;14:386. doi: 10.1186/1471-2334-14-386.

Cytokine secretion from brain macrophages infected with human immunodeficiency

virus in vitro and treated with raltegravir.

Tatro ET(1), Soontornniyomkij B, Letendre SL, Achim CL.

Author information:

(1)Department of Psychiatry, University of California San Diego, 9500 Gilman

Drive, La Jolla, San Diego, CA 92093-0603, USA. [email protected].

BACKGROUND: Integrase inhibitors are a promising class of antiretroviral drugs to

treat chronic human immunodeficiency virus (HIV) infection. During HIV infection,

macrophages can extravasate from the blood to the brain, while producing

chemotaxic proteins and cytokines, which have detrimental effects on central

nervous system cells. The main goal of this study was to understand the effects

of raltegravir (RAL) on human brain macrophage production of immune-mediators

when infected with HIV, but did not compare with other antiretroviral agents.

METHODS: Pro-inflammatory cytokines, IFN-γ, IL-10, IL-12-p70, IL-1, IL-8, TNF-α,

and IL-6 were measured simultaneously in tissue culture supernatants from primary

brain derived macrophages, microglia. We tested the effects of RAL on markers of

astrocytosis and neurite integrity in primary human neuroglial cultures.

RESULTS: RAL administered at 20 nM effectively suppressed HIV infection in

microglia over 9 days. Only IL-8, IL-10, and TNF-α were above the detection limit

in the majority of samples and RAL significantly suppressed the rate of cytokine

production in HIV-infected microglia. During RAL-alone, the rate of IL-8

secretion was higher.

CONCLUSIONS: RAL did not affect neurite area but inhibited astrocyte growth in

the neuroglial cultures. Exploring the effects of RAL on pro-inflammatory

molecule production in brain macrophages may contribute to designing ARV

neuroprotective strategies in chronic HIV infection.

PMCID: PMC4227040

PMID: 25015002  [PubMed - indexed for MEDLINE]

5. Biomaterials. 2014 Sep;35(28):8049-64. doi: 10.1016/j.biomaterials.2014.05.084.

Epub 2014 Jun 24.

The roles of blood-derived macrophages and resident microglia in the

neuroinflammatory response to implanted Intracortical microelectrodes.

Ravikumar M(1), Sunil S(1), Black J(2), Barkauskas DS(3), Haung AY(4), Miller

RH(5), Selkirk SM(6), Capadona JR(7).

Author information:

(1)Department of Biomedical Engineering, Case Western Reserve University, School

of Engineering, 2071 Martin Luther King Jr. Drive, Wickenden Bldg, Cleveland OH

44106, USA; Louis Stokes Cleveland Veterans Affairs Medical Center,

Rehabilitation Research and Development, Spinal Cord Injury Division, 10701 East

Blvd. Mail Stop 151 AW/APT, Cleveland OH 44106, USA. (2)Department of Biomedical

Engineering, Case Western Reserve University, School of Engineering, 2071 Martin

Luther King Jr. Drive, Wickenden Bldg, Cleveland OH 44106, USA. (3)Department of

Biomedical Engineering, Case Western Reserve University, School of Engineering,

2071 Martin Luther King Jr. Drive, Wickenden Bldg, Cleveland OH 44106, USA;

Department of Pediatrics, Case Western Reserve University School of Medicine,

Wolstein Research Building 6528, 2103 Cornell Rd, Cleveland, OH 44106, USA.

(4)Department of Pediatrics, Case Western Reserve University School of Medicine,

Wolstein Research Building 6528, 2103 Cornell Rd, Cleveland, OH 44106, USA.

(5)Department of Neurosciences, Case Western Reserve University, School of

Medicine, 10900 Euclid Ave, Sears Tower Bldg, Cleveland OH 44106, USA.

(6)Department of Neurology, Case Western Reserve University, School of Medicine,

11100 Euclid Avenue, Sears Tower Bldg, Cleveland OH 44106, USA; Louis Stokes

Cleveland Veterans Affairs Medical Center, Rehabilitation Research and

Development, Spinal Cord Injury Division, 10701 East Blvd. Mail Stop 151 AW/APT,

Cleveland OH 44106, USA. (7)Department of Biomedical Engineering, Case Western

Reserve University, School of Engineering, 2071 Martin Luther King Jr. Drive,

Wickenden Bldg, Cleveland OH 44106, USA; Louis Stokes Cleveland Veterans Affairs

Medical Center, Rehabilitation Research and Development, Spinal Cord Injury

Division, 10701 East Blvd. Mail Stop 151 AW/APT, Cleveland OH 44106, USA.

Electronic address: [email protected].

Resident microglia and blood-borne macrophages have both been implicated to play

a dominant role in mediating the neuroinflammatory response affecting implanted

intracortical microelectrodes. However, the distinction between each cell type

has not been demonstrated due to a lack of discriminating cellular markers.

Understanding the subtle differences of each cell population in mediating

neuroinflammation can aid in determining the appropriate therapeutic approaches

to improve microelectrode performance. Therefore, the goal of this study is to

characterize the role of infiltrating blood-derived cells, specifically

macrophages, in mediating neuroinflammation following intracortical

microelectrode implantation. Interestingly, we found no correlation between

microglia and neuron populations at the microelectrode-tissue interface. On the

other hand, blood-borne macrophages consistently dominated the infiltrating cell

population following microelectrode implantation. Most importantly, we found a

correlation between increased populations of blood-derived cells (including the

total macrophage population) and neuron loss at the microelectrode-tissue

interface. Specifically, the total macrophage population was greatest at two and

sixteen weeks post implantation, at the same time points when we observed the

lowest densities of neuronal survival in closest proximity to the implant.

Together, our results suggest a dominant role of infiltrating macrophages, and

not resident microglia, in mediating neurodegeneration following microelectrode

implantation.

Published by Elsevier Ltd.

PMCID: PMC4169074 [Available on 2015-09-01]

PMID: 24973296  [PubMed - in process]

6. Neurotherapeutics. 2014 Jul;11(3):679-95. doi: 10.1007/s13311-014-0277-y.

Bone marrow mesenchymal stromal cells drive protective M2 microglia polarization

after brain trauma.

Zanier ER(1), Pischiutta F, Riganti L, Marchesi F, Turola E, Fumagalli S, Perego

C, Parotto E, Vinci P, Veglianese P, D'Amico G, Verderio C, De Simoni MG.

Author information:

(1)Department of Neuroscience, IRCCS, Istituto di Ricerche Farmacologiche Mario

Negri, 20156, Milan, Italy.

Microglia/macrophages (M) are major contributors to postinjury inflammation, but

they may also promote brain repair in response to specific environmental signals

that drive classic (M1) or alternative (M2) polarization. We investigated the

activation and functional changes of M in mice with traumatic brain injuries and

receiving intracerebroventricular human bone marrow mesenchymal stromal cells

(MSCs) or saline infusion. MSCs upregulated Ym1 and Arginase-1 mRNA (p 

Have a look on these small review also. http://www.abcam.com/neuroscience/an-overview-of-microglia-subtypes-and-markers

I think you can do the flow to sort out microglia with high CD11b(microglia marker) and low CD45(microphage)

you can check our nature communication paper

MiR-9 promotes microglial activation by targeting MCPIP1