How are Macrophages Involved in Disease and Health?

Macrophages are antigen-presenting cells (APC) and tissue-resident professional phagocytes, which are formed as a result of the separation of circulating peripheral blood monocytes. They execute regulatory and active immune functions, as well as adaptive immunity [1].

Macrophages impact the outcome of various diseases; including, diabetes, autoimmune and allergic disorders, atherosclerosis, cancer, metabolic syndrome, and rheumatoid arthritis [2].

Primary human macrophages (MФ) are hard to separate from tissue in adequate amounts of a homogeneous phenotype, and they cannot proliferate in culture. Usually, the resulting cells show heterogeneous phenotypes. Highly pure human monocyte-derived macrophages (hMDM) are now commercially available, and can be cultured and activated in vitro. Therefore, they are an excellent alternative.

Old Nomenclature

Conventionally, activated macrophages of varied phenotypes have normally been divided into M2 and M1 macrophages. The “classically activated” M1-macrophages contain immune effector cells of an acutely inflammatory phenotype. They produce huge amounts of lymphokines and are extremely aggressive to bacteria [3]. On the contrary, the “alternatively activated” anti-inflammatory M2-macrophages execute many kinds of regulatory functions including maintaining tolerance, wound healing/tissue repair, and regulating immunity [1, 3]

Due to the functional heterogeneity of M2 macrophage functions, they have been allocated into three subgroups: M2a, M2b, and M2c.

As a matter of fact, cells of the monocyte/macrophage lineage have excellent plasticity in response to exogenous as well as endogenous stimuli, possibly even reversing the initial M1/M2 polarization processes [3]. For instance, M2 polarized macrophages can change to M1-activated status under specific conditions.

New Nomenclature

More recently, researchers have become aware that the conventional M1/M2 model does not adequately signify the entire complexity of the activation states of this highly plastic cell lineage [4]. In this regard, a mutual framework proposal for macrophage activation nomenclature was published by a group of international macrophage specialists [5]. It requires the designation of in vitro macrophage activation states in accordance with the stimulus used (for example, 20 ng/mL recombinant human (rhu) IL-4), while clearly signifying the differentiation factors used for generating MDM (for instance, 100 ng/mL rhu M-CSF). See also Table 1.

Table 1. Human macrophage activation reference table according to the common framework consensus nomenclature [5]. The published differentiation factor/activator combinations are presented here to serve as a basic guide. Specific effects of activation on macrophages should be tested in comparison to the most appropriate non-activated M(-)-baseline variant as a control

DEX = dexamethasone, IC = immune complexes, IFN = interferon, IgG = immunoglobulin G, GC = glucocorticoids, (G)M-CSF = (granulocyte/)macrophage colony stimulating factor, IL = interleukin, LPS = lipopolysaccharide, TAM = tumo- associated macrophages, TGF = transforming growth factor.

Activation state Former designation Differentiation factor (day 0+)* Activator (day 7+) Activation process reference
M1 M(IFN-y) M1 GM-CSF or M-CSF IFN-y (50ng/ml) [11]
M(LPS+IFN-y) M1 GM-CSF or M-CSF IFN-y (50ng/ml) + LPS (10ng/ml) [11]
M(LPS) M1 GM-CSF or M-CSF LPS (100ng/ml) [11]
M(-) M1, non-activated GM-CSF - [12]
M(-) M0 / M$ 2% human AB serum - [11, 13]
M(-) M2, non-activated M-CSF - [12]
M(GC) M2c M-CSF DEX (100nM) [12]
M(TGFþ) M2c M-CSF TGF-þ1 (20ng/ml) [12]
M(IL-10) M2c M-CSF IL-10 (10ng/ml) [14]
M(IC+LPS) M2b M-CSF IgG (immobilized) + LPS (100ng/ml) [15]
M2 M(IL-4) M2a M-CSF IL-4 (20ng/ml) [14, 15]

TAM M2-like Tumor microenvironment Tumor microenvironment [16]

*Use the differentiation factors M-CSF or GM-CSF at 50–100 ng/mL final concentration with Macrophage Base Medium DXF

For making purposeful and effective advances in macrophage-related research, defined and xeno-free macrophage culture systems, in tandem with the published guide principles for unified experimental standards for activation of macrophages in vitro, is necessary.

PromoCell provides a complete macrophage cell culture collection that includes media systems for separating tumor-associated macrophages (TAMs) from tumor tissues or producing macrophages from fresh peripheral blood mononuclear cells (PBMCs), assay-ready cryopreserved macrophages, and macrophage analysis tools for later use (Figure 1).

PromoCell macrophage cell culture portfolio. Overview of possible applications with PromoCell

Figure 1. PromoCell macrophage cell culture portfolio. Overview of possible applications with PromoCell's macrophage media and cryopreserved macrophages. More information is available on our web- site (Macrophage Generation Media DXF). Acronyms: IC = immune complexes, IFN = interferon, IgG = immuneglobulin G, GC = glucocorticoids, (G)M-CSF = (granulocyte/)macrophage colony stimulating factor, IL = interleukin, LPS = lipopolysaccharide, PBMC = peripheral blood mononuclear cells, TAM = tumor-associated macrophages (freshly isolated from tumor tissue), TGF = transforming growth factor.

Involvement of Macrophages in Health and Disease

Macrophages in Health

Macrophages exist in nearly all tissues and their function as antimicrobial phagocytes is widely-known. They play a role in several processes in a healthy organism, including wound healing, tissue homeostasis, infection, and development.

Tissue-resident macrophages have vital roles to play in human development and also perform inflammatory and homeostatic functions, such as regulating angiogenesis and removing apoptotic cells as secretions of inflammatory mediators [6].

However, the standard binary classification system (with M2 and M1macrophages) is becoming obsolete. Currently, interest is turning to the different kinds of functional phenotypes that are influenced by, and are extremely adaptive to, environmental stimuli.

Macrophages in Disease

Macrophages play a role in the establishment of many kinds of diseases, such as cancer, autoimmune disorders, and atherosclerosis (Figure 2). Generally, macrophages manifest as pro-inflammatory phenotypes during the early stages of infection and after that change to an anti-inflammatory state. If this initially helpful inflammatory reaction is not controlled, the macrophages become pathogenic, promote tissue damage, and contribute to the development of autoimmune or inflammatory diseases, among others [2].

Moreover, in cancers, there is a strong relationship between the macrophage transcriptional signature and macrophage density, and the survival rate of cancer patients [6]. An insight into the biological mechanisms, through which macrophages change between anti-inflammatory and inflammatory phenotypes, may play a vital role in describing the underlying pathologies of various chronic diseases [2].

Macrophage plasticity and polarization in different types of pathologies. Macrophages exhibit high plasticity and can switch between polarization/activation states. This enables them to perform different functions. For example, M1-like macrophages are more predominant in the early phases of inflammatory responses, whereas M2-like macrophages are more commonly associated with chronic inflammation processes. (RA = rheumatoid arthritis)Figure 2. Macrophage plasticity and polarization in different types of pathologies. Macrophages exhibit high plasticity and can switch between polarization/activation states. This enables them to perform different functions. For example, M1-like macrophages are more predominant in the early phases of inflammatory responses, whereas M2-like macrophages are more commonly associated with chronic inflammation processes. (RA = rheumatoid arthritis) [1, 17, 18]

Cancer

The macrophages are considered to have a controversial role in cancer and tumors. It has been shown in research that macrophages can either hinder or support tumorigenesis (Figure 3). Generally, it seems that M2 macrophage subsets assume an anti-inflammatory and pro-tumorigenic state, while M1 macrophage subsets tend to manifest as cytotoxic, pro-inflammatory, and anti-tumorigenic phenotypes [7].

Tumor microenvironment (TME). A tumor is surrounded by its own specific environment. In addition to having tumor-specific angiogenesis mechanisms, the TME comprises various cell types that make different contributions to tumor progression, e.g. tumor-associated macrophages or malignant cells.

Figure 3. Tumor microenvironment (TME). A tumor is surrounded by its own specific environment. In addition to having tumor-specific angiogenesis mechanisms, the TME comprises various cell types that make different contributions to tumor progression, e.g. tumor-associated macrophages or malignant cells.

Tumor-associated macrophages, or TAMs, are closer to M2 subsets. Moreover, TAMs seem to exhibit a huge diversity of sub-types, and as a result, the older binary nomenclature is quickly becoming outdated [7]. The latest experiments with TAMs as potential targets for cancer treatment have produced promising results; for example, by restricting the recruitment of monocytes, modulating the activation of TAMs, reprogramming TAMs and applying them as drug carriers [8].

Another method for reducing the immunosuppression of T cells and their cytotoxic functions is to inhibit the PD-1/PD-L1 signaling cascade with, for example, monoclonal antibodies (Figure 4). Macrophage phagocytosis is increased, tumor growth is reduced, and macrophage survival is prolonged by the inhibition of PD-1/PD-L1 signaling in vivo [9].

Generally, TAMs exhibit an immunosuppressive role in the progression of tumors [7]. For instance, in hypoxic regions of tumors, they exhibit more pronounced PD-L1 expression and promote the immunosuppression of T cells.

Reducing cancer cell- or tumor-as- sociated macrophage (TAM)-induced T cell immunosuppression. A) PD-L1 is more often expressed at higher levels in cancer cells or TAMs to modulate T cell-mediated cancer cell cytotoxicity. The tumor then creates an immunosuppressive microenvironment in which it can steadily grow. B) Antibodies act on the receptor or ligand to inhibit the PD-1/PD-L1 signaling cascade, thus interrupting T cell deactivation and reducing T cell-mediated immunosuppression.

Figure 4. Reducing cancer cell- or tumor-associated macrophage (TAM)-induced T cell immunosuppression. A) PD-L1 is more often expressed at higher levels in cancer cells or TAMs to modulate T cell-mediated cancer cell cytotoxicity. The tumor then creates an immunosuppressive microenvironment in which it can steadily grow. B) Antibodies act on the receptor or ligand to inhibit the PD-1/PD-L1 signaling cascade, thus interrupting T cell deactivation and reducing T cell-mediated immunosuppression.

In tumorigenesis, the roles played by TAMs range from promoting angiogenesis, metastasis, and immunosuppression, to interacting with cancer stem cells [7]. It has been demonstrated that macrophage metabolism can impact vessel morphogenesis and also the level of metastasis [10].

Inflammatory Diseases

Macrophages are involved in several chronic inflammatory and autoimmune diseases, such as rheumatoid arthritis, atherosclerosis, fibrosis, asthma, multiple sclerosis, and inflammatory bowel disease [2]. Usually, pro-inflammatory macrophages are considered the source of inflammatory cytokines and the successive pathological inflammation reaction. Macrophages executing a protective role have also been reported. Eventually, the mechanisms of macrophage polarization and differentiation in response to various microenvironments will be understood, allowing researchers to develop a deeper understanding of a wide spectrum of pathologies.

Perspectives

The transcriptional complexity, different origins, and adaptation of macrophage phenotypes to microenvironmental demands (pathology or homeostasis) are slowly being accepted, and are attracting a lot of interest. The determination of transcriptomes and proteomes of specific macrophage subsets may lead to a new classification system for macrophages on the basis of their functional phenotypes and origins [2]. Work has only just started to identify the broad array of human macrophages.

From a therapeutic point of view, macrophage targeting is a field that is highly pertinent and intensively researched. There may be significant potential in targeting macrophage markers and modulating chemokine/cytokine/growth factor expression. There is also potential in their production to treat macrophage-associated pathologies such as inflammatory and cancer diseases, for example, multiple sclerosis and rheumatoid arthritis (RA). One day, even obesity might be controlled by regulating and exploiting macrophage plasticity [2].

References

  1. Murray PJ and Wynn TA (2011). Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 11(11):723-737. doi: 10.1038/nri3073.
  2. Wynn TA et al (2013). Chawla, and J.W. Pollard, Macrophage biology in development, homeostasis, and disease. Nature 496(7446): 445-455. doi: 10.1038/nature12034.
  3. Murray PJ and Wynn TA (2011). Obstacles and opportunities for understanding macrophage polarization. J Leukoc Biol 89(4): 557-563. doi: 10.1189/jlb.0710409.
  4. Martinez FO and Gordon S (2014). The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep 6: 13. doi: 10.12703/P6-13.
  5. Murray PJ et al (2014). Macrophage Activation and Polarization: Nomenclature and Experimental Guidelines. Immunity 41(1): 14-20. doi: 10.1016/j.immuni.2014.06.008.
  6. Nielsen SR and Schmid MC (2017). Macrophages as Key Drivers of Cancer Progression and Metastasis. Mediators of inflammation 2017, Article ID 9624760, 11 pages. doi: 10.1155/2017/9624760.
  7. Aras S and Zaidi MR (2017). TAMeless traitors: macrophages in cancer progression and metastasis. Br J Cancer 117(11):1583-1591. doi: 10.1038/bjc.2017.356.
  8. Yang L and Zhang Y (2017). Tumor-associated macrophages, potential targets for cancer treatment. Biomark Res 5: 25.doi: 10.1186/s40364-017-0106-7.
  9. Fujimura T et al (2018). Tumor-Associated Macrophages: Therapeutic Targets for Skin Cancer. Front Oncol 8: 3.doi: 10.3389/fonc.2018.00003.
  10. Wenes M et al (2016). Macrophage Metabolism Controls Tumor Blood Vessel Morphogenesis and Metastasis. CellMetab 24(5): 701-715. doi: 10.1016/j.cmet.2016.09.008.
  11. Fujiwara Y et al (2016). Guanylate-binding protein 5 is a marker of interferon-gamma-induced classically activated macrophages. Clin Transl Immunology 5(11): e111. doi: 10.1038/cti.2016.59.
  12. Zizzo G et al (2012). Efficient clearance of early apoptotic cells by human macrophages requires M2c polarization and MerTK induction. J Immunol 189(7): 3508-20. doi: 10.4049/jimmunol.120066.
  13. Vogel DY et al (2014). Macrophages migrate in an activation-dependent manner to chemokines involved in neuroin- flammation. J Neuroinflammation 11: 23. doi: 10.1186/1742-2094-11-23.
  14. Iqbal S and Kumar A (2015). Characterization of In vitro Generated Human Polarized Macrophages. J Clin Cell Immu- nol 6: 6. doi: 10.4172/2155-9899.1000380.
  15. Graff JW et al (2012). Identifying functional microRNAs in macrophages with polarized phenotypes. J Biol Chem 287(26): 21816-25. doi: 10.1074/jbc.M111.327031.
  16. Sousa S et al (2015). Human breast cancer cells educate macrophages toward the M2 activation status. Breast Cancer Res 17: 101. doi: 10.1186/s13058-015-0621-0.
  17. Liu YC et al (2014). Macrophage Polarization in Inflammatory Diseases. Int J Biol Sci 10(5): 520-529. doi: 10.7150/ijbs.8879.
  18. Sica A and Mantovani A (2012). Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122(3): 787-795. doi: 10.1172/JCI59643.

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Last updated: May 22, 2019 at 3:32 AM

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