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Macrophages are a heterogeneous group of myeloid cells ubiquitously found in all mammalian tissues, where they perform diverse tasks depending on their location and gene expression profile and are involved in initiating and terminating inflammation. Tissue-resident macrophages (TRMs) usually originate from embryonic yolk sac or fetal liver precursors and maintain their numbers by self-renewal (Figure 1). Once developed, macrophages are influenced by their specific environment and can adopt a variety of phenotypes and activation states. For example, while Kupffer cells in the liver are primarily involved in waste disposal, alveolar macrophages in the lungs serve as the first line of defense against inhaled pathogens. In contrast, blood monocyte-derived macrophages make only a minor contribution to maintaining the balance of resident macrophages in the tissue. An exception is the intestine, which contains a large population of resident macrophages, that are all blood monocyte-derived (Italiani et al., 2014). The central nervous system (CNS) contains four types of macrophages. Microglia are found throughout the brain and play a role in CNS development and maturation and form the brain’s main line of defense. Perivascular macrophages, meningeal macrophages, and choroid plexus macrophages are strategically positioned at CNS barriers and support barrier function against external antigens (Li and Barres, 2018).
For an overview of the functions of mouse TRMs, see mouse-tissue-resident-macrophages.
Figure 1: Tissue-resident macrophages (TRMs) and monocyte-derived macrophages (MdMs) play distinct roles in tissue injury and repair. TRMs originate from the yolk sac and fetal liver and maintain their numbers by self-renewal. Few TRMs are derived from blood monocytes. In tissue homeostasis TRMs perform diverse tasks depending on their location. During injury, TRMs and MdMs play different roles: TRMs are implicated in initial recognition of tissue injury, whereas MdMs exhibit a more robust inflammatory response. During recovery from tissue injury, TRMs increase self-renewal and repopulate the tissue niche. MdMs only weakly contribute to this repopulation.
In inflammatory responses, initial recognition of infection or tissue damage is mediated by TRMs, which have a variety of receptors to recognize pathogen or danger-associated molecular patterns (Figure 1). As a result, TRMs are activated and produce neutrophil chemoattractants, e.g., CXCL1, CXCL2 or monocyte chemoattractant protein-1 (MCP-1) (Kumar et al., 2018). In the first wave of inflammation, neutrophils migrate to the site of inflammation, triggering a second inflammatory response that attracts monocytes and macrophages. (Kumar et al., 2018). Blood monocytes are recruited via CCL2/CCR2 or CX3CR1 pathways and the large majority of these cells give rise to the inflammatory monocyte-derived macrophages (MdMs) (Italiani et al., 2014). Activated TRM populations rapidly diminish, due to tissue emigration through draining lymphatics, cell death (Davies et al., 2013) and a reduced self-renewal capacity during acute inflammation (Mu et al., 2021). In the early stages of inflammation, macrophages initiate innate immunity by clearing apoptotic cells and presenting antigens to T-lymphocytes. A successful acute inflammatory response leads to the eradication of the infectious agents, followed by tissue repair by anti-inflammatory macrophages (Lee and Choi 2018). Anti-inflammatory macrophages appear usually from day three after the initial insult and are either derived from pro-inflammatory macrophages, which undergo a phenotypic switch, or recruited from blood monocytes (Bohaud et al., 2021). On recovery, TRMs repopulate inflamed tissues by increased local proliferation, with a concomitant reduction of infiltrated MdMs due to cell death (Davies et al., 2013, Mu et al., 2021). Few recruited MdMs persist, some gain the capacity for self-renewal and undergo a slow in situ phenotypic conversion to become TRMs (Watanabe et al., 2019; Mu et al., 2021). Excessive or unresolved macrophage activation can lead to pathogenic chronic inflammation, such as in atherosclerosis, diabetes, multiple sclerosis and amyotrophic lateral sclerosis.
To better describe macrophage functions, macrophages and microglia have been classified into either M1 or M2 based on stimulation type, surface molecule expression, cytokine secretion, and functional characteristics. This polarization nomenclature was introduced in 2000 following the Th1 / Th2 concept of T helper (Th) cells (Mills et al., 2000).
Monocytes from blood, bone marrow or spleen can be differentiated into macrophages (M0) in vitro (Figure 2). In response to different environmental stimuli, macrophages can either adopt a heal/growth-promoting (M2 macrophages) or a killing phenotype (M1 macrophages) (Figure 5).
Figure 2: Mouse bone marrow cells were differentiated into macrophages in the presence of macrophage colony-stimulating factor (M-CSF). Mouse bone marrow cells and differentiated macrophages were harvested, formalin-fixed and paraffin-embedded and stained with anti-F4/80 (HS-397 017, dilution 1:100; DAB). Nuclei were visualized with haematoxylin (blue). Less than 10% of cells in uncultured mouse bone marrow are F4/80 positive (left). During maturation, F4/80 expression increases, and in vitro differentiated M0 macrophages express high levels of F4/80 (right).
Classically activated M1 macrophages are formed in vitro in response to the cytokines interferon-γ (IFNγ) and tumor necrosis factor-alpha (TNFα) produced by Th1 cells, or by microbial products such as lipopolysaccharide (LPS) (Figure 3). The M1 phenotype is characterized by a high antigen presentation capacity and the production of nitric oxide (NO), chemokine ligand 9 (CXCL9) and interleukins IL-12 and IL-23. Mouse M1 macrophages can be identified by expression of CD38, G-protein coupled receptor 18 (Gpr18) and Formyl peptide receptor 2 (Fpr2) (Jablonski et al., 2015). LPS also leads to upregulation of the scavenger receptor MARCO (macrophage receptor with collagenous structure) (Chen et al., 2010), which plays a key role in the uptake of tumor cells (Xing et al., 2021).
Figure 3: Mouse macrophages were stimulated to force differentiation into M1 or M2a-like phenotypes. Cells were treated with LPS + IFNγ for an M1-like phenotype or with IL-4 for an M2a-like phenotype for 12 – 18 h. Stimulants were added directly to the medium, whereas no further stimulants were added to the culture for control cells (M0 macrophages). After the incubation period, the differentiated macrophages were harvested, formalin-fixed and paraffin-embedded. Different markers were used to monitor successful cell differentiation. First row: Immunohistochemical staining with rat anti-iNOS (cat. no. HS-484 017, 1:5000; DAB). High iNOS expression is detected in M1 macrophages differentiated in presence of IFNγ and LPS. Second row: Indirect immunostaining with rabbit anti-CD86 (cat. no. HS-466 003, 1:1000; DAB). High CD86 expression is detected in M1 macrophages differentiated in presence of IFNγ and LPS.
Alternatively activated M2 macrophages have diverse functions as effectors of parasite defense, possess immunoregulatory properties, promote tumor growth and invasiveness, and orchestrate tissue repair and remodeling (Lee and Choi, 2018). The M1/M2 model used to define macrophage polarization primarily identifies the extremes of a continuum and does not reflect the functional heterogeneity of M2 macrophages. Therefore, M2 macrophages are further subdivided into M2a, M2b, M2c and M2d subtypes (Mantovani et al., 2004; Ferrante et al., 2012) (Figure 5).
In this classification, the M2a subtype represents the prototypical IL-4 / IL-13 dependent subtype involved in clearance of apoptotic cells, modulation of the pro-inflammatory response, and wound healing. M2a macrophages highly express mannose receptor (CD206), decoy IL-1 receptor (IL-1R2) and CCL17 and secrete pro-fibrotic factors. However, significant differences exist between human and mouse macrophages in the expression of polarization markers. Reliable markers for identifying mouse M2a macrophages are Chil3 (YM-1) (Figure 4), Arg1 and FIZZ1 (Raes et al., 2002; Ferrante 2012), but these genes have no human homologs. In addition, Dectin-1/CLEC7A (Willment et al., 2003), early growth response protein 2 (Egr2) and c-Myc have been proposed as murine M2a-specific genes (Jablonski et al., 2015). Transglutaminase 2 (TGM2) is a unique functionally conserved M2a marker in both human and mice (Martinez et al., 2013).
Figure 4: Immunohistochemical staining of formalin-fixed paraffin-embedded cell pellets of in vitro differentiated mouse macrophages with rat anti-Chil3/YM-1 (cat. no. HS-442 017, dilution 1:1000; DAB). Chil3 expression is detected in alternatively activated M2a macrophages. Nuclei have been visualized by haematoxylin staining (blue).
M2b macrophages, also known as regulatory macrophages, can be induced by combined exposure to immune complexes (ICs) and TLR agonists or by IL-1R agonists. M2b macrophages highly express costimulatory molecules and are efficient antigen-presenting cells. M2b macrophages can be identified by the expression of sphingosine kinase 1 (Sphk1) and LIGHT/TNFSF14 (Edwards et al., 2006).
The anti-inflammatory M2c subtype of macrophages ("acquired deactivation macrophage") is induced by IL-10 via activating signal transducer and activator of transcription 3 (STAT3) (Wang et al., 2018). M2c macrophages express Mer tyrosine kinase (MerTK), which enables M2c macrophages to eliminate apoptotic cells more efficiently than other macrophage subtypes (Zizzo et al., 2012).
The angiogenic M2d subtype results from adenosine-dependent ‘‘switching’’ of M1 macrophages. The M2d subtype is characterized by a reduced release of pro-inflammatory cytokines with an upregulation of IL-10 and the potent angiogenic molecule vascular endothelial growth factor (VEGF) (Ferrante et al., 2012). This subtype is also known as a tumor-associated macrophage (TAM) and represents the major inflammatory component in neoplastic tissue (Duluc et al., 2007). TAMs have potent immunosuppressive functions, low antigen presentation capacity, and promote the recruitment of Tregs, Th2 cells and naïve T cells through secretion of chemokine ligands CCL17, CCL22 and CCL18. Leukemia inhibitory factor (LIF) and IL-6 are tumor microenvironment factors that can promote TAM generation from blood-derived monocytes (Duluc et al., 2007). Human macrophages differentiated in the presence of LIF and IL-6 exhibit a CD14high CD163high CD80low CD86low ILT2high ILT3high phenotype (Duluc et al., 2007).
Traditionally, microglia are thought to be in a quiescent M0 state under physiological conditions and activated under pathological conditions. Like macrophages, microglia can polarize into the pro-inflammatory M1 phenotype or the anti-inflammatory M2 phenotype in response to different micro-environmental stimuli. (Figure 6).
In vitro, M1 microglia are differentiated in the presence of interferon-gamma (IFNγ) or lipopolysaccharide (LPS). M1 microglia mainly secrete pro-inflammatory cytokines, e.g., tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), IL-12, and produce reactive oxygen species (ROS) and nitric oxide (NO) by expressing nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and inducible NO-synthase (iNOS). M1 microglia highly express MHCII, CD86, CD40 and Fcγ receptors (CD16/CD32) to enable antigen presentation, integrins (CD11b and CD11c) and co-stimulatory molecules (CD36, CD45, CD47) (Colonna and Butovsky, 2017; Zhou et al., 2017). M1 microglia induce inflammation and neurotoxicity.
Analogous to macrophages, the M2 state characterizes the anti-inflammatory and healing microglia phenotype and is further subdivided into alternative activated M2a, transition activated M2b and acquired deactivation M2c states (Colonna and Butovsky, 2017). The M2a phenotype is involved in immunity to parasites and tissue repair and produces anti-inflammatory cytokines. The M2b phenotype shares features with M1 microglia and expresses the M1-associated cell surface proteins CD86 and MHCII (Wendimu and Hooks, 2022). M2c microglia mediate the removal of myelin debris and are involved in remyelination. In contrast to Wnt5a secreting M1 microglia, M2c microglia secrete large amounts of Wnt7a (Mecha et al., 2020) (table 2).
| Activation | Cell Marker | Secreted Proteins | |
| M1 | IFN-γ LPS |
NADPH oxidase iNOS MHCII CD86 CD11b CD11c CD36 CD45 CD47 CD16/32 CD40 |
TNF-α, IL-6, IL-1β, IL-12, CCL2 IL-12/IL-23 CCL5/CCL11 MMP12 Wnt5a |
| M2a | IL-4 IL-13 |
CD206 Arg-1 (mouse) |
Chil3/YM-1 (mouse) FIZZ1 (mouse) |
| M2b | TLR IL-1R |
MHCII CD86 |
IL-10 (high), IL-12 (low) COX-2 |
| M2c | IL-10 glucocorticoids TGF-β |
CD163 CD206 Arg-1 (mouse) |
TGFβ IL-10 Wnt7a |
Can macrophages and microglia be so easily divided into M1 and M2 in vivo? The simple answer is no.
The M1/M2 paradigm is an in vitro model based on stimulating macrophages, microglia or cell lines in culture with a specific set of factors. Following the M1/M2 model, tissue-resident macrophages are often classified as M2-like. However, in vitro results are already difficult to compare. In in vitro experiments, the expression of common macrophage polarization markers is strongly influenced by the type of cells used to generate macrophages, e.g., monocytic cell lines or primary cells from blood or bone marrow. Microglia and TRMs are strongly influenced by their tissue environment, and cultured peritoneal macrophages and microglia have been shown to completely lose their tissue-specific gene expression program after a 7-day incubation period (Gosselin et al., 2014). Furthermore, in vitro differentiation of macrophages is significantly affected by different culture conditions (Wang et al., 2022) and stimulation duration (Purcu et al., 2022). Optimal stimulation times for specific macrophage polarization markers vary widely, leading to false-negative results and making it difficult to compare different studies (Purcu et al., 2022). The in vitro environment and stimuli used to differentiate the cells, e.g., M-CSF and GM-CSF, primes and activates macrophages before they are even stimulated in the M1 or M2 phenotypes. GM-CSF leads to a more pro-inflammatory state (TNF expression), and M-CSF induces a tissue healing state (IL-10 expression) after LPS stimulation (Orecchioni et al., 2019).
Figure 7: Fluorescent detection of F4/80 (HS-397 004, 1:1000; white), CD163 (HS-455 003, 1:500, red) and iNos (HS-484 017, 1:1000; green) in non-infected (healthy) and T.gondii infected mouse liver using the tyramide signal amplification (TSA) method. CD163 and F4/80 co-localize in large Kupffer macrophages in healthy mouse liver. In infected liver, macrophages lose CD163 expression. Inducible Nos (iNOS) is detected in foci of hepatocellular necrosis.
Figure 8: Fluorescent detection of F4/80 (HS-397 017, 1:250; white), CD86 (HS-466 003, 1:500, red) and CD11b (HS-384 308, 1:1000; green) in non-infected (healthy) and T.gondii infected mouse liver using the tyramide signal amplification (TSA) method. Neither CD86- nor CD11b-positive cells are detected in healthy mouse liver. In infected liver, CD11b-positive mononuclear cells and CD86-expressing cells are located in or near foci of hepatocellular necrosis.
In vivo, macrophages exist beyond the dichotomy of M1/M2 subtypes and can express markers for both M1 and M2 subtypes (Oates et al., 2022). Macrophage polarization is more complex than the binary M1 and M2 model, and the M1 and M2 states represent only the extremes of the spectrum. M2 macrophages can still express M1 markers, but to a lower extent than M1 macrophages and vice versa (Boutilier and Elsawa, 2021). In vivo, LPS-treated macrophages have been shown to regulate few genes exactly like in vitro differentiated macrophages, and some genes and pathways are even oppositely regulated. This may be due to the use of immature macrophage precursors in in vitro studies, e.g., from bone marrow, which are not found in peripheral tissues (Orecchioni et al., 2019).
Microglia are the first line of defense in the CNS and must receive a continuous “everything is well” signal from surrounding cells to maintain immune surveillance. When a mild injury occurs, cells at the injury site send a “find me” signal, and microglial cells rapidly enter the M2 state. M2 microglial cells are characterized by distal branching and small cell body-like changes and promote cell tissue repair and regeneration. If severe or persistent tissue damage occurs, the cells send an “eat me” signal and the microglial cells are activated into an amoeboid or round cell body state with thick protrusions – the pro-inflammatory or toxic M1 phenotype. However, the M1/M2 nomenclature is far too simplistic for describing in vivo situations. Microglia differentiation occurs in vivo even in the absence of infection, e.g., after trauma or ischemic reperfusion. This suggests the presence of alternative stimuli (Wang et al., 2023). Genome-wide expression profiling studies highlight the complexity of microglia phenotypes, showing mixed M1/M2 phenotypes in aging and pathological disease models. Transitional phenotypes have been observed, e.g., in mouse models of traumatic brain injury (TBI) or retinal degeneration (Wendimu and Hooks, 2022). In acute inflammatory responses, activated microglia are characterized by upregulation of CD11b, ICAM-1, P-selectin, major histocompatibility complex II (MHCII), CD80 (T-cell costimulatory molecules B7–1), CD86 (T-cell costimulatory molecules B7–2), and CD40 (a member of the tumor necrosis factor (TNF) receptor) (Lima et al., 2022). Galectin-3 (Gal-3) is only expressed in activated microglia (Figure 9) and is an emerging target for modulating microglia activation in neurodegenerative diseases (Garcia-Revilla et al., 2022).
Figure 9: Chromogenic double-staining of Galectin-3 (Cat. HS-477 017, 1:1000; DAB; brown) and Abeta38/40/42/43 (Cat. 218 008, 1:1000; AP-RED; red) in a mouse model of Alzheimer’s disease (APP PS1). Galectin-3 expressing activated microglia cells are located near Aβ plaques. Nuclei have been visualized with haematoxylin (blue).
In steady-state, Microglia already exhibit different phenotypic signatures due to brain-specific regional differences (Böttcher et al., 2019). In addition, microglia diversify during early development, during aging, exhibit sex differences and show different subsets in response to disease pathology (Tremblay 2021). Currently, several microglia subtypes are proposed, namely “satellite” microglia located on the axon side of the neuron cell body, keratin sulfate-positive KSPG microglia around motor neurons, CD11c microglia in neonatal mice, Hoxb8-positive microglia, “microglia supporting neurogenesis” and “dark” microglia (reviewed in Wang et al., 2023).
In summary, macrophages and microglia cannot be simply divided into M1 and M2, good and evil, or ugly and beautiful. Rather, the spectrum seems to include all conceivable M1/M2 mixed phenotypes.
| Cat. No. | Product Description | Application | Quantity | Price | Cart |
|---|
HS-384 018 | CD11b, rabbit, monoclonal, recombinant IgGrecombinant IgG human specific | WB IHC-P | 100 µl | $415.00 |   |
| HS-384 103 | CD11b, rabbit, polyclonal, affinity purifiedaffinity mouse specific | WB ICC IHC IHC-P | 200 µl | $450.00 | |
| HS-384 117 | CD11b, rat, monoclonal, purified IgG IgG mouse specific | WB IHC IHC-P IHC-Fr | 200 µl | $415.00 | |
| HS-384 117BT | CD11b, rat, monoclonal, purified IgG IgG, biotin | WB IHC-P | 100 µg | $465.00 | |
| 375-0P | CD11c, control peptidecontrol peptide | 100 µg | $105.00 | | |
| HS-375 003 | CD11c, rabbit, polyclonal, affinity purifiedaffinity | WB IHC IHC-P | 200 µl | $370.00 | |
| HS-375 004 | CD11c, Guinea pig, polyclonal, antiserumantiserum | WB IHC IHC-P | 100 µl | $350.00 | |
| HS-375 017 | CD11c, rat, monoclonal, purified IgG IgG | IHC IHC-P IHC-Fr | 100 µg | $415.00 | |
| HS-455 003 | CD163, rabbit, polyclonal, affinity purifiedaffinity mouse specific | WB IHC IHC-P | 200 µl | $370.00 | |
| HS-455 013 | CD163, rabbit, polyclonal, affinity purifiedaffinity human specific | IHC-P | 50 µg | $370.00 | |
| HS-495 017 | CD169, rat, monoclonal, purified IgG IgG mouse specific | IHC IHC-P | 100 µg | $415.00 | |
| HS-488 003 | CD206, rabbit, polyclonal, affinity purifiedaffinity | WB IHC IHC-P | 50 µg | $370.00 | |
| HS-493 017 | CD39, rat, monoclonal, purified IgG IgG mouse specific | WB IHC IHC-P | 100 µg | $415.00 | |
| HS-460 003 | CD68, rabbit, polyclonal, affinity purifiedaffinity | WB IHC IHC-P | 50 µg | $370.00 | |
| HS-460 008 | CD68, rabbit, monoclonal, recombinant IgGrecombinant IgG human specific | WB IHC-P | 100 µl | $415.00 | |
| HS-460 017 | CD68, rat, monoclonal, purified IgG IgG human specific | WB ICC IHC-P | 200 µl | $415.00 | |
| HS-466 003 | CD86, rabbit, polyclonal, affinity purifiedaffinity mouse specific | WB IHC IHC-P | 50 µg | $370.00 | |
| HS-442 017 | Chil3 / YM1, rat, monoclonal, purified IgG IgG mouse specific | WB ICC IHC IHC-P | 100 µg | $415.00 | |
| HS-442 117 | Chil3 / YM1, rat, monoclonal, purified IgG IgG mouse specific | WB ICC IHC IHC-P | 100 µg | $415.00 | |
| HS-501 003 | CLEC4F, rabbit, polyclonal, affinity purifiedaffinity C-terminal | WB IHC IHC-P | 50 µg | $370.00 | |
| HS-501 103 | CLEC4F, rabbit, polyclonal, affinity purifiedaffinity N-terminal | WB IHC IHC-P | 50 µg | $370.00 | |
| HS-397 004 | F4/80, Guinea pig, polyclonal, antiserumantiserum | IHC IHC-P | 100 µl | $350.00 | |
| HS-397 008 | F4/80, rabbit, monoclonal, recombinant IgGrecombinant IgG | WB IHC IHC-P | 100 µl | $415.00 | |
| HS-397 017 | F4/80, rat, monoclonal, purified IgG IgG | WB IHC IHC-P IHC-Fr | 200 µl | $415.00 | |
| HS-397 017BT | F4/80, rat, monoclonal, purified IgG IgG, biotin | WB IHC-P | 100 µg | $465.00 | |
| HS-477 017 | Galectin-3, rat, monoclonal, purified IgG IgG K.O. mouse specific | WB IHC IHC-P IHC-Fr | 100 µg | $415.00 | |
| HS-234 008 | IBA1, rabbit, monoclonal, recombinant IgGrecombinant IgG | WB ICC IHC IHC-P | 100 µl | $420.00 | |
| HS-234 013 | IBA1, rabbit, polyclonal, affinity purifiedaffinity K.O. | WB IHC IHC-P | 200 µl | $380.00 | |
| HS-234 017 | IBA1, rat, monoclonal, purified IgG IgG | WB ICC IHC IHC-P | 200 µl | $415.00 | |
| HS-234 017BT | IBA1, rat, monoclonal, purified IgG IgG, biotin | WB IHC-P | 100 µg | $465.00 | |
| HS-234 308 | IBA1, Guinea pig, monoclonal, recombinant IgGrecombinant IgG | WB ICC IHC IHC-P | 50 µg | $425.00 | |
| HS-484 017 | iNOS, rat, monoclonal, purified IgG IgG mouse specific | WB IHC-P | 100 µg | $415.00 | |
| HS-499 003 | MARCO, rabbit, polyclonal, affinity purifiedaffinity mouse-specific | WB IHC IHC-P | 50 µg | $370.00 | |
| End of List |
Author: Dr. Christel Bonnas
Scientific Director of HistoSure
Christel has a strong background in immunology and histopathology. She is responsible for antibody development, validation and quality control of our HistoSure product line.
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Orecchioni et al., 2019. Macrophage Polarization: Different Gene Signatures in M1(LPS+) vs. Classically and M2(LPS–) vs. Alternatively Activated Macrophages. PMID: 31178859
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Wang et al., 2023. A richer and more diverse future for microglia phenotypes. PMID: 37025898
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