Macrophage polarization

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Macrophage polarization is a process by which macrophages adopt different functional programs in response to the signals from their microenvironment. This ability is connected to their multiple roles in the organism: they are powerful effector cells of the innate immune system, but also important in removal of cellular debris, embryonic development and tissue repair. [1]

Contents

By simplified classification, macrophage phenotype has been divided into 2 groups: M1 (classically activated macrophages) and M2 (alternatively activated macrophages). This broad classification was based on in vitro studies, in which cultured macrophages were treated with molecules that stimulated their phenotype switching to a particular state. [2] In addition to chemical stimulation, it has been shown that the stiffness of the underlying substrate a macrophage is grown on can direct polarization state, functional roles and migration mode. [3] A continuum of M1-M2 polarization may arise even in the absence of polarizing cytokines and differences in substrate stiffness. [4] M1 macrophages were described as the pro-inflammatory type, important in direct host-defense against pathogens, such as phagocytosis and secretion of pro-inflammatory cytokines and microbicidal molecules. M2 macrophages were described to have quite the opposite function: regulation of the resolution phase of inflammation and the repair of damaged tissues. Later, more extensive in vitro and ex vivo studies have shown that macrophage phenotypes are much more diverse, overlapping with each other in terms of gene expression and function, revealing that these many hybrid states form a continuum of activation states which depend on the microenvironment. [5] [6] [7] [8] Moreover, in vivo, there is a high diversity in gene expression profile between different populations of tissue macrophages. [9] Macrophage activation spectrum is thus considered to be wider, involving complex regulatory pathway to response to plethora of different signals from the environment. [10] [11] The diversity of macrophage phenotypes still remain to be fully characterized in vivo.

The imbalance of the macrophage types is related to a number of immunity-related diseases. [12] [13] For example, it has been shown that increased M1/M2 ratio correlates with development of inflammatory bowel disease, [14] [15] as well as obesity in mice. [16] [17] [18] On the other side, in vitro experiments implicated M2 macrophages as the primary mediators of tissue fibrosis. [13] Several studies have associated the fibrotic profile of M2 macrophages with the pathogenesis of systemic sclerosis. [12] [19]

Types

M1

Classically activated macrophages (M1) were named by G. B. Mackaness in the 1960s. [20] M1-activation in vitro is evoked by treatment with TLR ligands such as bacterial lipopolysaccharide (LPS) - typical for Gram-negative bacteria and lipoteichoic acid (LTA) - typical for Gram-positive bacteria, granulocyte-macrophage colony-stimulating factor (GM-CSF) or combination of LPS and interferon-gamma (IFN-γ). [2] [21] [22] Similarly in vivo, classically activated macrophages arise in response to IFN-γ produced by Th1 lymphocytes or by natural killer cells (NK), and tumor-necrosis factor (TNF), produced by antigen-presenting cells (APCs). [22]

M1-activated macrophages express transcription factors such as interferon regulatory factor (IRF5), nuclear factor of kappa light polypeptide gene enhancer (NF-κB), activator protein (AP-1) and STAT1. This leads to enhanced microbicidal capacity and secretion of high levels of pro-inflammatory cytokines: e.g. IFN-γ, IL-1, IL-6, IL-12, IL-23 and TNFα. Moreover, to increase their pathogen-killing ability, they produce increased amounts of chemicals called reactive oxygen species (ROS) and nitrogen radicals (caused by upregulation of inducible NO synthase iNOS). [5] [23] Thanks to their ability to fight pathogens, M1 macrophages are present during acute infectious diseases. A number of studies have shown that bacterial infection induces polarization of macrophages toward the M1 phenotype, resulting in phagocytosis and intracellular killing of bacteria in vitro and in vivo. For instance, Listeria monocytogenes , a Gram-positive bacteria causing listeriosis is shown to induce an M1 polarization, [24] [25] as well as Salmonella Typhi (the agent of typhoid fever) and Salmonella Typhimurium (causing gastroenteritis), which are shown to induce the M1 polarization of human and murine macrophages. [25] Macrophages are polarized toward the M1 profile during the early phase of Mycobacterium tuberculosis infection, [26] as well as other mycobacterial species such as Mycobacterium ulcerans (causing Buruli ulcer disease) and Mycobacterium avium. [25]

Improper and untimely control of M1 macrophage-mediated inflammatory response can lead to disruption of normal tissue homeostasis and impede vascular repair. An uncontrolled production of pro-inflammatory cytokines during the inflammation can lead to the formation of cytokine storm, thereby contributing to the pathogenesis of severe sepsis. [27] In order to counteract the inflammatory response, macrophages undergo apoptosis or polarize to an M2 phenotype to protect the host from the excessive injury. [23]

M2

Alternatively activated macrophages (M2) were discovered in early 1990s and named according to previously-discovered Th2 cell-mediated anti-inflammatory response. [23] M2 macrophages resolve inflammation, help tissue healing, tolerate self-antigens and certain neoantigens (for example apoptotic cells, symbiont cells, gametes and cells of the embryo in the uterus). M2 macrophages hence govern functions at the interfaces of immunity, tissue development and turnover, metabolism, and endocrine signaling. [28] It is shown in vitro that macrophage treatment with IL-4 and IL-13 leads to inhibition of pro-inflammatory signals production and upregulation of scavenging mannose receptor CD206. [23] Further studies have shown that M2 polarization may be induced through different activation signals leading in fact to different M2 phenotypes having different roles. It has first been suggested that M2 macrophages can be divided in two groups: regulatory and wound-healing macrophages. Regulatory macrophages were described to have anti-inflammatory properties, which are important in resolutive phases of the inflammation, producing the immunosuppressive cytokine IL-10. Differentiation toward the regulatory macrophage phenotype may be triggered by immune complexes, prostaglandins, apoptotic cells and IL-10. On the other side, wound healing macrophages were shown to produce IL-4 and upregulate arginase activity, which is the enzyme enrolled in production of polyamines and collagen, thus regenerating the damaged tissue. [5] [6]

Further investigation of M2 subtypes led to even more complex systematization, where the authors describe M2a, M2b, and M2c subtype. [7] [12] M2a macrophages are activated by IL-4 and IL-13 which evokes upregulated expression of arginase-1, mannose receptor MRc1 (CD206), antigen presentation by MHC II system, and production of IL-10 and TGF-𝛽, leading to tissue regeneration and internalization of pro-inflammatory molecules to prevent the inflammatory response. The M2b macrophages produce IL-1, IL-6, IL-10, TNF-𝛼 as a response to immune complexes or LPS, leading to activation of Th2 cells and anti-inflammatory activity. M2c macrophages are activated by IL-10, transforming growth factor beta (TGF-𝛽) and glucocorticoids, and produce IL-10 and TGFβ, leading to suppression of inflammatory response. Some authors mention the M2d subtype activation as a response to IL-6 and adenosines, and these macrophages are also referred as tumor-associated macrophages (TAM). [7] [12] [29]

Although M2 activation state involves heterogeneous macrophage populations, some markers are shared between subtypes, thus the strict macrophage division into subtypes is not possible so far. In mice, CD206 or the mannose receptor marker can be used to differentiate the M2 from M1. Moreover, the in vivo translation of these M2 subdivisions is difficult. Tissues contain complex range of stimuli leading to mixed macrophage populations with a wide spectrum of activation states. [7] [30]

Continuum of polarization states

A lot remains to be learned about macrophage polarized activation states and their role in immune response. Since there is not a rigid barrier between described macrophage phenotypes and that known markers are expressed by more than one of these activation states, [5] [30] it is impossible so far to classify macrophage subtypes in proper and precise way. Thus their differences are rather considered as a continuum of functional states without clear boundaries. Moreover, it is observed that macrophage states are changing during the time course of the inflammation and disease. [30] [31] This plasticity of macrophage phenotype has added to the confusion regarding the existence of individual macrophage sub-types in vivo. [30] [32]

Tumour associated macrophages

Tumour-associated macrophages (TAM) are typical for their protumoural functions like promotion of cancer cell motility, metastasis formation and angiogenesis [33] and their formation is dependent on microenvironmetal factors which are present in developing tumour. [34] TAMs produce immunosuppressive cytokines like IL-10, TGFβ and PGE2 very small amount of NO or ROI and low levels of inflammatory cytokines (IL-12, IL-1β, TNFα, IL-6). [35] Ability of TAMs to present tumour-associated antigens is decreased as well as stimulation of the anti-tumour functions of T and NK cells. Also TAMs are not able to lyse tumour cells. [34] Targeting of TAM may be a novel therapeutic strategy against cancer, as has been demonstrated through the delivery of agents to either alter the recruitment and distribution of TAMs, [36] deplete existing TAMs, [37] or induce the re-education of TAMs from an M2 to an M1 phenotype. [38] [39]

Tissue resident macrophages

Some macrophages are known to be residing in the tissues and help in maintaining the tissue microenvironment. These came to be known as tissue resident macrophages(TRMs). The TRMs in the pancreatic islets are known to be inflammatory in nature and fall under the M1 category. [40]

Related Research Articles

<span class="mw-page-title-main">Inflammation</span> Physical effects resulting from activation of the immune system

Inflammation is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, and initiate tissue repair.

<span class="mw-page-title-main">Macrophage</span> Type of white blood cell

Macrophages are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris, and foreign substances, which do not have proteins that are specific to healthy body cells on their surface. This process is called phagocytosis, which acts to defend the host against infection and injury.

<span class="mw-page-title-main">Interleukin 4</span> Mammalian protein found in Mus musculus

The interleukin 4 is a cytokine that induces differentiation of naive helper T cells (Th0 cells) to Th2 cells. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4 in a positive feedback loop. IL-4 is produced primarily by mast cells, Th2 cells, eosinophils and basophils. It is closely related and has functions similar to IL-13.

Stromal cells, or mesenchymal stromal cells, are differentiating cells found in abundance within bone marrow but can also be seen all around the body. Stromal cells can become connective tissue cells of any organ, for example in the uterine mucosa (endometrium), prostate, bone marrow, lymph node and the ovary. They are cells that support the function of the parenchymal cells of that organ. The most common stromal cells include fibroblasts and pericytes. The term stromal comes from Latin stromat-, "bed covering", and Ancient Greek στρῶμα, strôma, "bed".

<span class="mw-page-title-main">Integrin alpha M</span> Mammalian protein found in Homo sapiens

Integrin alpha M (ITGAM) is one protein subunit that forms heterodimeric integrin alpha-M beta-2 (αMβ2) molecule, also known as macrophage-1 antigen (Mac-1) or complement receptor 3 (CR3). ITGAM is also known as CR3A, and cluster of differentiation molecule 11B (CD11B). The second chain of αMβ2 is the common integrin β2 subunit known as CD18, and integrin αMβ2 thus belongs to the β2 subfamily integrins.

<span class="mw-page-title-main">Interleukin 19</span> Protein-coding gene in the species Homo sapiens

Interleukin 19 (IL-19) is an immunosuppressive protein that belongs to the IL-10 cytokine subfamily.

Pyroptosis is a highly inflammatory form of lytic programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. This process promotes the rapid clearance of various bacterial, viral, fungal and protozoan infections by removing intracellular replication niches and enhancing the host's defensive responses. Pyroptosis can take place in immune cells and is also reported to occur in keratinocytes and some epithelial cells.

<span class="mw-page-title-main">TREM1</span> Protein-coding gene in the species Homo sapiens

Triggering receptor expressed on myeloid cells 1 (TREM1) an immunoglobulin (Ig) superfamily transmembrane protein that, in humans, is encoded by the TREM1 gene. TREM1 is constitutively expressed on the surface of peripheral blood monocytes and neutrophils, and upregulated by toll-like receptor (TLR) ligands; activation of TREM1 amplifies immune responses.

<span class="mw-page-title-main">MARCO</span> Protein-coding gene in the species Homo sapiens

Macrophage receptor with collagenous structure (MARCO) is a protein that in humans is encoded by the MARCO gene. MARCO is a class A scavenger receptor that is found on particular subsets of macrophages. Scavenger receptors are pattern recognition receptors (PRRs) found most commonly on immune cells. Their defining feature is that they bind to polyanions and modified forms of a type of cholesterol called low-density lipoprotein (LDL). MARCO is able to bind and phagocytose these ligands and pathogen-associated molecular patterns (PAMPs), leading to the clearance of pathogens and cell signaling events that lead to inflammation. As part of the innate immune system, MARCO clears, or scavenges, pathogens, which leads to inflammatory responses. The scavenger receptor cysteine-rich (SRCR) domain at the end of the extracellular side of MARCO binds ligands to activate the subsequent immune responses. MARCO expression on macrophages has been associated with tumor development and also with Alzheimer's disease, via decreased responses of cells when ligands bind to MARCO.

A macrophage-activating factor (MAF) is a lymphokine or other receptor based signal that primes macrophages towards cytotoxicity to tumors, cytokine secretion, or clearance of pathogens. Similar molecules may cause development of an inhibitory, regulatory phenotype. A MAF can also alter the ability of macrophages to present MHC I antigen, participate in Th responses, and/or affect other immune responses.

An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include interleukin-1 (IL-1), IL-6, IL-12, and IL-18, tumor necrosis factor alpha (TNF-α), interferon gamma (IFNγ), and granulocyte-macrophage colony stimulating factor (GM-CSF) and play an important role in mediating the innate immune response. Inflammatory cytokines are predominantly produced by and involved in the upregulation of inflammatory reactions.

Tumor-associated macrophages (TAMs) are a class of immune cells present in high numbers in the microenvironment of solid tumors. They are heavily involved in cancer-related inflammation. Macrophages are known to originate from bone marrow-derived blood monocytes or yolk sac progenitors, but the exact origin of TAMs in human tumors remains to be elucidated. The composition of monocyte-derived macrophages and tissue-resident macrophages in the tumor microenvironment depends on the tumor type, stage, size, and location, thus it has been proposed that TAM identity and heterogeneity is the outcome of interactions between tumor-derived, tissue-specific, and developmental signals.

Adipose tissue macrophages comprise tissue resident macrophages present in adipose tissue. Adipose tissue apart from adipocytes is composed of the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular endothelial cells and variety of immune cells. The latter ones are composed of mast cells, eosinophils, B cells, T cells and macrophages. The number of macrophages within adipose tissue differs depending on the metabolic status. As discovered by Rudolph Leibel and Anthony Ferrante et al. in 2003 at Columbia University, the percentage of macrophages within adipose tissue ranges from 10% in lean mice and humans up to 50% in extremely obese, leptin deficient mice and almost 40% in obese humans. Increased number of adipose tissue macrophages correlates with increased adipose tissue production of proinflammatory molecules and might therefore contribute to the pathophysiological consequences of obesity.

Mucosal-associated invariant T cells make up a subset of T cells in the immune system that display innate, effector-like qualities. In humans, MAIT cells are found in the blood, liver, lungs, and mucosa, defending against microbial activity and infection. The MHC class I-like protein, MR1, is responsible for presenting bacterially-produced vitamin B2 and B9 metabolites to MAIT cells. After the presentation of foreign antigen by MR1, MAIT cells secrete pro-inflammatory cytokines and are capable of lysing bacterially-infected cells. MAIT cells can also be activated through MR1-independent signaling. In addition to possessing innate-like functions, this T cell subset supports the adaptive immune response and has a memory-like phenotype. Furthermore, MAIT cells are thought to play a role in autoimmune diseases, such as multiple sclerosis, arthritis and inflammatory bowel disease, although definitive evidence is yet to be published.

Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells, derived from common lymphoid progenitors (CLPs). In response to pathogenic tissue damage, ILCs contribute to immunity via the secretion of signalling molecules, and the regulation of both innate and adaptive immune cells. ILCs are primarily tissue resident cells, found in both lymphoid, and non- lymphoid tissues, and rarely in the blood. They are particularly abundant at mucosal surfaces, playing a key role in mucosal immunity and homeostasis. Characteristics allowing their differentiation from other immune cells include the regular lymphoid morphology, absence of rearranged antigen receptors found on T cells and B cells, and phenotypic markers usually present on myeloid or dendritic cells.

Neuroinflammation is inflammation of the nervous tissue. It may be initiated in response to a variety of cues, including infection, traumatic brain injury, toxic metabolites, or autoimmunity. In the central nervous system (CNS), including the brain and spinal cord, microglia are the resident innate immune cells that are activated in response to these cues. The CNS is typically an immunologically privileged site because peripheral immune cells are generally blocked by the blood–brain barrier (BBB), a specialized structure composed of astrocytes and endothelial cells. However, circulating peripheral immune cells may surpass a compromised BBB and encounter neurons and glial cells expressing major histocompatibility complex molecules, perpetuating the immune response. Although the response is initiated to protect the central nervous system from the infectious agent, the effect may be toxic and widespread inflammation as well as further migration of leukocytes through the blood–brain barrier may occur.

Regulatory macrophages (Mregs) represent a subset of anti-inflammatory macrophages. In general, macrophages are a very dynamic and plastic cell type and can be divided into two main groups: classically activated macrophages (M1) and alternatively activated macrophages (M2). M2 group can further be divided into sub-groups M2a, M2b, M2c, and M2d. Typically the M2 cells have anti-inflammatory and regulatory properties and produce many different anti-inflammatory cytokines such as IL-4, IL-33, IL-10, IL-1RA, and TGF-β. M2 cells can also secrete angiogenic and chemotactic factors. These cells can be distinguished based on the different expression levels of various surface proteins and the secretion of different effector molecules.

<span class="mw-page-title-main">Dermal macrophage</span> Skin macrophages used for wound repair and hair growth

Dermal macrophages are macrophages in the skin that facilitate skin homeostasis by mediating wound repair, hair growth, and salt balance. Their functional role in these processes is the mediator of inflammation. They can acquire an M1 or M2 phenotype to promote or suppress an inflammatory response, thereby influencing other cells' activity via the production of pro-inflammatory or anti-inflammatory cytokines. Dermal macrophages' ability to acquire pro-inflammatory properties also potentiates them in cancer defence. M1 macrophages can suppress tumour growth in the skin by their pro-inflammatory properties. However, M2 macrophages support tumour growth and invasion by the production of Th2 cytokines such as TGFβ and IL-10. Thus, the exact contribution of each phenotype to cancer defence and the skin's homeostasis is still unclear.

<span class="mw-page-title-main">Smoker's macrophages</span>

Smoker’s macrophages are alveolar macrophages whose characteristics, including appearance, cellularity, phenotypes, immune response, and other functions, have been affected upon the exposure to cigarettes. These altered immune cells are derived from several signaling pathways and are able to induce numerous respiratory diseases. They are involved in asthma, chronic obstructive pulmonary diseases (COPD), pulmonary fibrosis, and lung cancer. Smoker’s macrophages are observed in both firsthand and secondhand smokers, so anyone exposed to cigarette contents, or cigarette smoke extract (CSE), would be susceptible to these macrophages, thus in turns leading to future complications.

Immune system contribution to regeneration of tissues generally involves specific cellular components, transcription of a wide variety of genes, morphogenesis, epithelia renewal and proliferation of damaged cell types. However, current knowledge reveals more and more studies about immune system influence that cannot be omitted. As the immune system exhibits inhibitory or inflammatory functions during regeneration, the therapies are focused on either stopping these processes or control the immune cells setting in a regenerative way, suggesting that interplay between damaged tissue and immune system response must be well-balanced. Recent studies provide evidence that immune components are required not only after body injury but also in homeostasis or senescent cells replacement.

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