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Neuroprotective Therapy for Stroke and Ischemic Disease pp 303–328Cite as

Polarization of Microglia/Macrophages in Brain Ischaemia: Relevance for Stroke Therapy

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Part of the book series: Springer Series in Translational Stroke Research ((SSTSR))

Abstract

The innate immune system plays a pivotal role in ischemic stroke pathobiology, involving soluble and cellular mediators activated locally or recruited from the periphery. Upon injury, subtle modifications of the local environment trigger a rapid activation of microglia that peaks few days after the insult and may persist for several weeks. Initially, the alternatively activated M2 phenotype predominates, whereas, upon priming by ischemic neurons, microglia shift towards the M1 phenotype characterized by reduced phagocytic capacity and release of inflammatory cytokines. Maximally activated microglia can eventually turn into a round amoeboid phenotype morphologically indistinguishable from blood-derived macrophages.

A typical hallmark of cerebral ischaemia is the increased permeability of cerebral microvessels that, together with the upregulation of adhesion molecules on post-capillary venules and the choroid plexus, facilitate brain recruitment of leukocytes. Bone marrow-derived monocytes rapidly extravasate via a chemokine receptor 2 [CCR2]-dependent pathway and, once in the injured tissue, differentiate into non-inflammatory M2 macrophages, mediating neuroprotection and repair of the neurovascular unit. M2 macrophages peak few days after the insult in the core region, whereas the pro-inflammatory M1 phenotype predominates in the peri-infarct areas to gradually increase in number in the core, outnumbering M2 cells over time. The dualistic role exerted by microglia/macrophages suggests that a mere inhibition of their activation/recruitment might not represent a promising strategy to rescue ischemic brain injury. By contrast, as thoroughly reviewed here, a rational modulation of their polarization status, aimed at adjusting the M1/M2 ratio coherently with the spatio-temporal progression of injury, has recently been validated in animal models.

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Abbreviations

ATP:

Adenosine 5′-triphosphate

BBB:

Blood–brain barrier

BDNF:

Brain-derived neurotrophic factor

CB:

Cannabinoid receptor

CCL2:

Monocyte chemoattractant protein-1

CCR2:

CC chemokine receptor 2

CNS:

Central nervous system

CXCR1:

Fractalkine receptor

DAMPs:

Danger-associated molecular patterns

GDNF:

Glia-derived neurotrophic factor

GFP:

Green fluorescent protein

IGF:

Insulin-like growth factor

IL:

Interleukin

IL-1R:

Interleukin-1 receptor

INF:

Interferon

Ly6C:

Lymphocyte antigen 6 complex, locus C

MCAo:

Middle cerebral artery occlusion

MCP:

Monocyte chemoattractant protein

MHC:

Major histocompatibility complex

MIP:

Macrophage inflammatory protein

miRNAs:

MicroRNAs

MMPs:

Matrix metalloproteinases

MR:

Mineralcorticoid receptor

nAChR:

Nicotinic acetylcholine receptor

PACAP:

Pituitary adenylate cyclase-activating polypeptide

PBMCs:

Peripheral blood mononuclear cells

PPAR:

Peroxisome proliferator-activated receptor

PRRs:

Pattern recognition receptors

ROS:

Reactive oxygen species

RXR:

Retinoid X receptor

SR-A:

Class A scavenger receptor

TGF:

Transforming growth factor

TLR:

Toll-like receptor

TNF:

Tumour necrosis factor

TREM:

Triggering receptor expressed on myeloid cells

USPIO:

Ultrasmall superparamagnetic iron oxide particles

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Authors and Affiliations

  1. Section of Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Calabria, Italy

    Diana Amantea Ph.D. & Giacinto Bagetta

  2. Laboratory of Neurophysiology of Integrative Autonomic Systems, Headache Science Centre, “C. Mondino” National Neurological Institute, Pavia, Italy

    Rosaria Greco & Cristina Tassorelli

  3. Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy

    Cristina Tassorelli

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  1. Diana Amantea Ph.D.
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  2. Rosaria Greco
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  3. Cristina Tassorelli
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  4. Giacinto Bagetta
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Correspondence to Diana Amantea Ph.D. .

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  1. Department of Neurology and Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA

    Paul A. Lapchak

  2. Loma Linda University School of Medicine, Loma Linda, California, USA

    John H. Zhang

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Amantea, D., Greco, R., Tassorelli, C., Bagetta, G. (2017). Polarization of Microglia/Macrophages in Brain Ischaemia: Relevance for Stroke Therapy. In: Lapchak, P., Zhang, J. (eds) Neuroprotective Therapy for Stroke and Ischemic Disease. Springer Series in Translational Stroke Research. Springer, Cham. https://doi.org/10.1007/978-3-319-45345-3_12

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  • DOI: https://doi.org/10.1007/978-3-319-45345-3_12

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  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-45344-6

  • Online ISBN: 978-3-319-45345-3

  • eBook Packages: MedicineMedicine (R0)

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