Macrophage Activation and Polarization: Nomenclature and Experimental Guidelines

Murray, Peter J.; Allen, Judith E.; Biswas, Subhra K.; Fisher, Edward A.; Gilroy, Derek W.; Goerdt, Sergij; Gordon, Siamon; Hamilton, John A.; Ivashkiv, Lionel B.; Lawrence, Toby; Locati, Massimo; Mantovani, Alberto; Martínez, Fernando O.; Mège, Jean‐Louis; Mosser, David M.; Natoli, Gioacchino; Saeij, Jeroen P. J.; Schultze, Joachim L.; Shirey, Kari Ann; Sica, Antonio; Suttles, Jill; Udalova, Irina A.; Ginderachter, Jo A. Van; Vogel, Stefanie N.; Wynn, Thomas A.

doi:10.1016/j.immuni.2014.06.008

Cited by 4,539 publications

(3,832 citation statements)

References 49 publications

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“…When proposing that Kv1.3 inhibitors preferentially inhibit “M1‐like” inflammatory microglia/macrophage functions and preserve beneficial “M2‐like” functions, we are fully cognizant of the fact that microglia are highly plastic and, unlike T‐cells, do not achieve stable differentiation states 48. Yet, our results seem to support this simple therapeutic hypothesis by showing that the observed reduction in infarct area and improvement in neurological deficit following PAP‐1 treatment is accompanied by a reduction in brain levels of IL‐1 β and IFN‐ γ , but not IL‐10 and BDNF or an impairment of phagocytosis.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the potassium channel Kv1.3 reduces infarction and inflammation in ischemic stroke

Chen

Nguyen

Maezawa

et al. 2017

Ann Clin Transl Neurol

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ObjectiveInhibitors of the voltage‐gated K+ channel Kv1.3 are currently in development as immunomodulators for the treatment of autoimmune diseases. As Kv1.3 is also expressed on microglia and has been shown to be specifically up‐regulated on “M1‐like” microglia, we here tested the therapeutic hypothesis that the brain‐penetrant small‐molecule Kv1.3‐inhibitor PAP‐1 reduces secondary inflammatory damage after ischemia/reperfusion.MethodsWe studied microglial Kv1.3 expression using electrophysiology and immunohistochemistry, and evaluated PAP‐1 in hypoxia‐exposed organotypic hippocampal slices and in middle cerebral artery occlusion (MCAO) with 8 days of reperfusion in both adult male C57BL/6J mice (60 min MCAO) and adult male Wistar rats (90 min MCAO). In both models, PAP‐1 administration was started 12 h after reperfusion.ResultsWe observed Kv1.3 staining on activated microglia in ischemic infarcts in mice, rats, and humans and found higher Kv1.3 current densities in acutely isolated microglia from the infarcted hemisphere than in microglia isolated from the contralateral hemisphere of MCAO mice. PAP‐1 reduced microglia activation and increased neuronal survival in hypoxia‐exposed hippocampal slices as effectively as minocycline. In mouse MCAO, PAP‐1 dose‐dependently reduced infarct area, improved neurological deficit score, and reduced brain levels of IL‐1β and IFN‐γ without affecting IL‐10 and brain‐derived nerve growth factor (BDNF) levels or inhibiting ongoing phagocytosis. The beneficial effects on infarct area and neurological deficit score were reproduced in rats providing confirmation in a second species.InterpretationOur findings suggest that Kv1.3 constitutes a promising therapeutic target for preferentially inhibiting “M1‐like” inflammatory microglia/macrophage functions in ischemic stroke.

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Section: Discussionmentioning

confidence: 99%

Inhibition of the potassium channel Kv1.3 reduces infarction and inflammation in ischemic stroke

Chen

Nguyen

Maezawa

et al. 2017

Ann Clin Transl Neurol

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“…4). IL-4 is well known to up-regulate 15-LOX-1 (49), and this has been included as a criterion for M2 differentiation (3). Apparently, initiation of Mf polarization in M2 direction by M-CSF is sufficient to up-regulate 15-LOX-1, thus increasing the capacity for formation of lipoxins and resolvins.…”

Section: Discussionmentioning

confidence: 99%

“…A major issue in Mf biology is to characterize functional phenotypes, currently described as a heterogeneous spectrum of activated states, from M1 to M2 (3,4). Stimulating factors, such as cytokines and pathogens, can induce specific phenotypes: originally IFN-g + LPS activation resulted in a proinflammatory M1 state, whereas IL-4 activation induced the alternatively activated M2 state.…”

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confidence: 99%

GM‐CSF– and M‐CSF–primed macrophages present similar resolving but distinct inflammatory lipid mediator signatures

et al. 2017

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M1 and M2 activated macrophages (Mfs) have different roles in inflammation. Because pathogens may first encounter resting cells, we investigated lipid mediator profiles prior to full activation. Human monocytes were differentiated with granulocyte Mf colony-stimulating factor (GM-CSF) or Mf colony-stimulating factor (M-CSF), which are known to prime toward M1 or M2 phenotypes, respectively. Lipid mediators released during resting conditions and produced in response to bacterial stimuli (LPS/N-formylmethionyl-leucyl-phenylalanine or peptidoglycan) were quantified by liquid chromatography-mass spectrometry. In resting conditions, both Mf phenotypes released primarily proresolving lipid mediators (prostaglandin E 2 metabolite, lipoxin A 4 , and 18-hydroxyeicosapentaenoic acid). A striking shift toward proinflammatory eicosanoids was observed when the same cells were exposed (30 min) to bacterial stimuli: M-CSF Mfs produced considerably more 5-lipoxygenase products, particularly leukotriene C 4 , potentially linked to M2 functions in asthma. Prostaglandins were formed by both Mf types. In the M-CSF cells, there was also an enhanced release of arachidonic acid and activation of cytosolic phospholipase A 2 . However, GM-CSF cells expressed higher levels of 5-lipoxygenase and 5-lipoxygenase-activating protein, and in ionophore incubations these cells also produced the highest levels of 5-hydroxyeicosatetraenoic acid. In summary, GM-CSF and M-CSF Mfs displayed similar proresolving lipid mediator formation in resting conditions but shifted toward different proinflammatory eicosanoids upon bacterial stimuli. This demonstrates that preference for specific eicosanoid pathways is primed by CSFs before full M1/M2 activation.-Lukic, A., Larssen, P., Fauland, A., Samuelsson, B., Wheelock, C. E., Gabrielsson, S., Radmark, O. GM-CSF-and M-CSF-primed macrophages present similar resolving but distinct inflammatory lipid mediator signatures. FASEB J. 31, 4370-4381 (2017). www.fasebj.orgMacrophages (Mfs) orchestrate the inflammatory process from early onset to the resolution phase (1, 2). A major issue in Mf biology is to characterize functional phenotypes, currently described as a heterogeneous spectrum of activated states, from M1 to M2 (3, 4). Stimulating factors, such as cytokines and pathogens, can induce specific phenotypes: originally IFN-g + LPS activation resulted in a proinflammatory M1 state, whereas IL-4 activation induced the alternatively activated M2 state. Polarized cells express distinct markers, such as transcription factors, cytokines, and surface markers; these are the main tools to define Mf phenotypes. A number of transcripts have been reported to differ between M1 and M2 Mfs, including mRNAs for enzymes involved in eicosanoid metabolism (5).Eicosanoids originate from arachidonic acid (AA), released from membrane phospholipids by phospholipases, typically cytosolic phospholipase A 2 (cPLA 2 ) (6). Free AA is further metabolized via 3 enzymatic pathways: lipoxygenase (LO), cyclooxygenase (COX), and cyto...

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“…The study described focused on in vitro characterization of rabbit macrophages of different phenotypes, which could expand the scope of in vitro methods for polarization of human and mouse macrophages. The study also provides additional experimental data to further develop experimental guidelines for macrophage activation and classification 28.…”

Section: Discussionmentioning

confidence: 99%

Rabbit M1 and M2 macrophages can be induced by human recombinant GM‐CSF and M‐CSF

Yamane

Leung

2016

FEBS Open Bio

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Macrophages can change their phenotype in response to environmental cues. Polarized macrophages are broadly classified into two groups: classical activated M1 and alternative activated M2. Characterization of human macrophages has been widely studied, but polarized macrophages in rabbits have not been characterized. We characterized rabbit macrophages that were polarized using human recombinant GM‐CSF and M‐CSF. GM‐CSF‐treated macrophages had higher mRNA expression of proinflammatory cytokines (M1 phenotype) than did the M‐CSF‐treated counterpart. By contrast, high levels of TGF‐β and IL‐10 expression (M2 phenotype) were found in M‐CSF‐treated macrophages. The present study may be useful to understand roles of polarized macrophages in rabbit disease models.

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Macrophage Activation and Polarization: Nomenclature and Experimental Guidelines

Cited by 4,539 publications

References 49 publications

Inhibition of the potassium channel Kv1.3 reduces infarction and inflammation in ischemic stroke

Inhibition of the potassium channel Kv1.3 reduces infarction and inflammation in ischemic stroke

GM‐CSF– and M‐CSF–primed macrophages present similar resolving but distinct inflammatory lipid mediator signatures

Rabbit M1 and M2 macrophages can be induced by human recombinant GM‐CSF and M‐CSF

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