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Editorial

The M1/M2 immune polarization concept in

microglia: a fair transfer?

Michel Mittelbronn
Institute of Neurology (Edinger Institute), Goethe University, D‑60528 Frankfurt am Main, Germany.

Although macrophages were first described in 1882 research. Although there was a lack of substantial
by Ilya Ilyich Metchnikoff, it was 30 years before the data, direct transfer of the immune polarization idea
first descriptions of monocytes, their relatives within to microglial cells was frequently performed without
the blood stream. [1,2] Initially described as a phagocytic further testing its applicability. More recent studies
cell mainly within the context of tissue inflammation, made it increasingly evident that microglial cells and
it took until the turn of the millennium to introduce blood-derived macrophages display considerably
the alternative myeloid cell (MØ) immune polarization different phenotypes upon similar stimulation
[3]
[6]
concept, which was provided by Mills et al. in 2000. conditions. In particular, M2 conditions, which
This concept of differential M1-M2 polarization of MØ typically induce CD163 and CD206 in macrophages,
was deduced from the classical dichotomic activation failed to result in a similar phenotype in microglial cells.
program of lymphocytes. Furthermore, in central nervous system (CNS) disorders,
such as Alzheimer’s disease, the immune polarization
However, it was an oversimplified idea to attribute MØ state of microglial cells is not solely dependent on the
activation to the so-called Th1-lymphocytes producing microenvironmental immune milieu, it is also strongly
interferon-γ while MØ inhibition was ascribed to related to the amyloid beta deposit subtype (oligomeric
Th2-lymphocytes secreting high levels of interleukin or fibrillar forms). A more recent study demonstrated
[7]
10, among other cytokines. It was demonstrated that that autopsy cases of Alzheimer’s disease display
lymphocytes determine the activation state of MØ, and M1-polarized MØs in very early stages, while more severe
MØ strongly influences the differential activation state of stages with increased levels of neuritic plaques (and
lymphocytes. Because it was shown that MØ stimulated often accompanied with extensive cerebrovascular
[4]
by Th1-lymphocytes secreted high levels of nitric oxide, pathology) displayed a M2a-polarized subtype.
[8]
thereby leading to a reduced proliferative potential, the Other findings in animal models of neurodegenerative
M1-M2 concept was quickly adapted to other paradigms, disorders, such as the mutant superoxide dismutase
such as tumor-associated macrophages (TAM) or tissue model for amyotrophic lateral sclerosis, revealed that
[5]
repair mechanisms. In general, M1-polarized TAMs were M2-polarized microglia were neuroprotective, but
regarded as immune cells with tumor-suppressive capacity, M1-polarized microglia were neurotoxic. Notably,
[9]
whereas M2-polarized TAMs are tumor promoting. the first experimental treatment approaches revealed
that chronic neurodegenerative changes related to
The M1-M2 concept also quickly attracted the attention microglial activation can be attenuated via minocycline,
of many neuroscientists working in immunological a substance inhibiting microglial activation, which leads
to increased activation of the M2-polarized microglial
Access this article online phenotype. [10] However, there is also opposing data
Quick Response Code: claiming that activated microglia do not specifically
Website: up-regulate molecules of either the M1- or M2-polarized
www.nnjournal.net
phenotype; rather they show an increase on both axes.
[11]
DOI:
10.4103/2347-8659.135567 Nevertheless, many authors simply classify myeloid
immune cells in the CNS under the combined term as

Corresponding Author: Dr. Michel Mittelbronn, Institute of Neurology (Edinger Institute), Goethe University, D‑60528 Frankfurt am
Main, Germany. E‑mail: michel.mittelbronn@kgu.de

6 Neuroimmunol Neuroinflammation | Volume 1 | Issue 1 | June 2014