He also observed cells that were able to uptake particles that had been placed in the digestive tracts of the larvae. Elie Metchnikoff coined these cells as phagocytes and later called them white blood cells for their first-line-of-defense role against infection in living organisms 1.
Later, the term macrophage was introduced by Aschoff in to designate a set of cells of the reticuloendothelial system formed not only by monocytes, macrophages, and histiocytes, but also by fibroblasts, endothelial, and reticular cells. After , the concept of the mononuclear phagocyte system — formed by a variety of macrophages derived from monocytes from the bone marrow — was introduced to replace the concept of the reticuloendothelial system, which is constituted of functionally and immunologically distinct cells.
Most macrophages are derived from bone marrow precursor cells that develop into monocytes. These are formed in the bone marrow from stem cells of the granulocytic—monocytic lineage that are exposed to cytokines such as the granulocyte macrophage colony stimulating factor GM-CSF and interleukin-3 IL Differentiation from stem cells is associated with the expression of specific membrane receptors for cytokines.
In normal healthy adults, the half-life of a circulating monocyte is estimated at 70 h. After crossing the walls of capillaries into connective tissue, monocytes turn into macrophages. This differentiation process involves many changes as the cell increases in size from 5 to 10 times, its organelles increase both in number and complexity, phagocytic capacity increases, etc. It is important to note that not all macrophages, such as Langerhans cells and brain microglia, develop from monocytes 2.
The main function of macrophages is to engulf foreign agents that enter the body. These include microbes and other particulate matter. In addition, they eliminate apoptotic cells and recycle nutrients by digesting waste products from tissues. Macrophages are hence essential not only for immunity, but also for development and tissue homeostasis 2. These cells are normally at rest, but can be activated by a variety of stimuli during the immune response 3 , 4.
In addition, these multifaceted cells are also capable of chemotaxis, namely the process of being attracted and displaced to a particular location by specific molecules. Besides phagocytosis, macrophages play a central role in inflammation. They initiate the immune response against microorganisms, since macrophages are some of the first cells to come in contact with these invaders.
This is in part due to their toll-like and scavenger receptors, which have broad ligand specificity for lectins, lipoproteins, proteins, oligonucleotides, polysaccharides, and other molecules. In addition to these functions, macrophages express major histocompatibility complex MHC class II molecules on their membranes, and as such, also present antigens to lymphocytes.
When macrophages engulf a microbe, its antigens are processed and situated on the outer surface of the plasmalemma, where they will be recognized by T helper cells. Following this recognition, T lymphocytes release cytokines that activate B cells, and activated B lymphocytes then secrete antibodies specific to the antigens presented by the macrophage. These antibodies attach to antigens on microbes, or to cells invaded by microbes; in turn, these antibody-bound complexes are phagocytosed more avidly by macrophages.
Cytokines and chemokines are potent signaling molecules that are as important to life as hormones and neurotransmitters. They are low molecular weight proteins that mediate intercellular communication and are produced by many cell types, primarily those of the immune system.
They were discovered in the early 60—70s, and today, over different proteins are known as cytokines 5. These molecules orchestrate a variety of processes ranging from the regulation of local and systemic inflammation to cellular proliferation, metabolism, chemotaxis, and tissue repair. In other organisms, such as fruit flies and lizards 6 , cytokine-like molecules are known to regulate host defense and temperature homeostasis.
The primary function of cytokines is to regulate inflammation, and as such, play a vital role in regulating the immune response in health and disease. There are proinflammatory and anti-inflammatory cytokines. Each cytokine binds to a specific cell surface receptor to generate a cell signaling cascade that affects cell function. This includes the positive or negative regulation of several genes and their transcription factors.
Each cytokine is produced by a cell population in response to different stimuli; they induce an array of agonist, synergistic, or antagonistic effects that functionally alter target cells.
A primary feature of cytokine biology is that of functional redundancy: different cytokines share similar functions. Furthermore, cytokines are pleiotropic since they act on many different cell types, and cells may express more than one receptor for a given cytokine.
To generalize the effect of a particular cytokine is virtually impossible. Cytokines are classified as paracrine if the action in the vicinity of the place of release is restricted, autocrine if the cytokine acts on the cell that secretes it, and endocrine if the cytokine reaches remote regions of the body. Most cytokines are short-lived and act locally in an autocrine and paracrine fashion.
Cytokines are mainly produced by macrophages and lymphocytes, although they can also be produced by polymorphonuclear leukocytes PMN , endothelial and epithelial cells, adipocytes, and connective tissue. Cytokines are essential to the functions of macrophages.
Multiple subsets of macrophages have been characterized depending on the origin and microenvironment in which the macrophage is found. Contingent on activation status, macrophages have been classified as classically and alternatively activated. In turn, these different macrophage types drastically differ in the cytokines that they secrete, and consequently, their functions 8.
The process of cytokine secretion is masterfully regulated by a series of interorganellar exchanges that rely on vesicular trafficking and cytoskeletal remodeling 9. Proteins regulating neurotransmitter release, notably members of the soluble N -ethylmaleimide-sensitive factor attachment protein receptor SNARE family 9 , 10 , and more recently synaptotagmins Syt 11 , are pivotal for the spatiotemporal regulation of cytokine secretion.
In immune cells, SNAREs and Syts have been found to regulate processes ranging from cytokine trafficking to cell migration and phagocytosis. This review will present the functions of macrophage cytokines and, where known, summarize findings on how these cytokines are released.
The types of macrophages that secrete these cytokines will also be depicted. To illustrate the importance of macrophage cytokines in health and disease, we will describe selected examples of how pathogens use cytokines to their advantage. Although monocytes and macrophages are the main sources of these cytokines, they are also produced by activated lymphocytes, endothelial cells, and fibroblasts.
Additionally, macrophages release chemokines, leukotrienes, prostaglandins, and complement. All of these molecules, in concert, may induce increased vascular permeability and recruitment of inflammatory cells. Aside from local effects, these mediators also produce systemic effects such as fever and the production of acute inflammatory response proteins.
The inflammatory response is beneficial for the host when the aforementioned cytokines are produced in appropriate amounts, but toxic when produced in a deregulated fashion.
It stimulates the acute phase of the immune response. This potent pyrogenic cytokine is one of the first to be released in response to a pathogen, and is able to exert its effects in many organs As such, TNF is one of the main cytokines responsible for septic shock.
In the hypothalamus, TNF stimulates the release of corticotropic releasing hormone, suppresses appetite, and induces fever. In liver, it stimulates the acute inflammatory response by elevating the synthesis of C-reactive protein and other mediators. TNF induces vasodilation and loss of vascular permeability, which is propitious for lymphocyte, neutrophil, and monocyte infiltration. It helps recruit these cells to the inflammation site by regulating chemokine release.
This in turn increases CXCR2-dependent neutrophil migration to the inflammation site. Being an inducer of the inflammatory response, excess amounts of TNF have been found to play pathological roles in ailments such as inflammatory bowel disease, psoriasis, rheumatoid arthritis, asthma, cancer, infectious diseases, and other auto-immune pathologies.
Some of these conditions are currently co-treated with monoclonal antibodies that neutralize this cytokine In macrophages, TNF is released to the extracellular milieu via the constitutive secretion pathway, and its trafficking is the best understood of all cytokines 9 , 17 , Details on TNF trafficking will be discussed in another article of this issue. Rho1 and Cdc42, two proteins that govern cell shape via actin remodeling, also regulate the post-recycling endosome trafficking of TNF to the plasmalemma Moreover, LPS was found to increase the expression of vesicle trafficking proteins that regulate TNF trafficking 17 , The process of phagocytosis requires extensive membrane exocytosis from several organelles that also partake in TNF secretion 7.
Interestingly, it was found that TNF is not only secreted to the extracellular milieu at the plasma membrane, but also in a polarized manner at the phagocytic cup This highlights an efficient and elegant strategy where macrophages can promptly release cytokines at the same time that they phagocytose microbial invaders.
The importance of regulating TNF secretion implies that there exist negative regulators for its secretion. One such regulator is the recently characterized protein Syt XI, which associates to recycling endosomes and lysosomes in macrophages 11 , Syts constitute a group of membrane proteins that regulate vesicle docking and fusion in processes such as exocytosis 11 , 23 and phagocytosis 11 , 24 , However, Syt XI cannot bind calcium and inhibits vesicle fusion The inverse is true when Syt XI is overexpressed It is also a chemoattractant for granulocytes, enhances the expansion and differentiation of CD4 T cells 29 , and increases the expression of cell adhesion molecules on leukocytes and endothelial cells.
IL-1Ra is secreted via the classical secretory, though the exact mechanism is not well known. It can also exert its effects in an intracrine fashion and act as a transcription factor 29 , After activation, autophagy plays a major role in the release of this cytokine.
Autophagy is a highly conserved process in eukaryotes in which the cytoplasm, aberrant, or damaged organelles are sequestered in double-membrane vesicles and released into the lysosome for breakdown and eventual recycling of resulting macromolecules This process plays a crucial role in adaptation to changing environmental conditions, starvation, cellular remodeling during development, and senescence.
Autophagy is characterized by the formation of double-membrane vesicles, called autophagosomes, which capture and transport cytoplasmic material to acidic compartments where material is degraded by hydrolytic enzymes Additionally, exocytosis of P2X7R-positive multivesicular bodies containing exosomes has also been reported to play an important role in the release of this cytokine The various modes of IL-1 secretion highlight the exquisite machinery that macrophages have evolved as a means for rapidly responding to inflammatory stimuli.
IL-6 is a pleiotropic cytokine that has both proinflammatory and anti-inflammatory functions that affect processes ranging from immunity to tissue repair and metabolism.
It promotes differentiation of B cells into plasma cells, activates cytotoxic T cells, and regulates bone homeostasis. Proinflammatory properties are elicited when IL-6 signals in trans via soluble IL-6 receptors binding to gp, which is ubiquitous in all cells. Inhibition of trans signaling via gp blockade in murine sepsis models rescues mice from widespread inflammation and death IL-6 trans signaling also leads to recruitment of monocytes to the inflammation site 42 , promotes the maintenance of Th17 cells, and inhibits T cell apoptosis and development of Tregs In contrast, anti-inflammatory properties are elicited when IL-6 signals through the classical pathway, which occurs via the IL-6 receptor that only few cells express.
IL-6 classic signaling also mediates apoptosis inhibition and the regeneration of intestinal epithelial cells IL-6 is a soluble cytokine that is synthesized in the ER and, unlike TNF, is not processed as a membrane-bound precursor.
Golgi-derived vesicles then fuse with VAMP3-positive recycling endosomes. Three-dimensional reconstruction of fluorescence images showed that recycling endosomes can harbor both TNF and IL-6, albeit both occupy different subcompartments IL is produced primarily by monocytes, macrophages, and other antigen-presenting cells; it is essential for fighting infectious diseases and cancer. IL is a heterodimeric cytokine comprised of the p35 and p40 subunits, which come together after their synthesis.
Deletions within the p40 gene have been observed in patients suffering from concurrent multiple bacterial infections 46 , IL promotes cell-mediated immunity via stimulation of Th1 cells. The involvement of this cytokine in these processes has made it a target in both auto-immune pathologies and cancer 46 , After protein synthesis, both p40 and p35 subunits associate at the ER, where they undergo subsequent glycosylation steps prior to being released at the cell membrane Although the precise post-Golgi trafficking mechanisms in macrophages are not known, the release route is likely to resemble that of TNF and IL-6 9.
Furthermore, IL is secreted in a polarized manner from lymphocytes; this process is dependent on Cdc42 52 , which also regulates release of TNF to the plasma membrane. This raises the interesting prospect that IL may be released in a polarized fashion, along with TNF 17 , at nascent macrophage phagosomes. It is similar to IL in that both induce inflammation. IL is a member of the IL family, and is composed of subunits p28 and Epstein—Barr virus-induced gene 3.
IL also has anti-inflammatory properties, which are exemplified by the fact that IL receptor-deficient mice are more susceptible to auto-immune encephalomyelitis, which correlates with increased levels of Th17 cells The fact that this cytokine has selective inflammatory and anti-inflammatory properties supports the concept that the inflammatory response is prompt, but also carefully calibrated to avoid damage to the host.
Inflammation is tightly regulated by multiple inhibitors and antagonists. IL is a 35 kD cytokine identified in , and is produced by activated macrophages, B cells, and T cells IL suppresses MHC-II expression in activated macrophages and is thus a potent inhibitor of antigen presentation Experiments in murine models have shown that blocking or neutralizing IL leads to increased levels of TNF and IL-6; on the contrary, exogenous IL improves survival and reduces the levels of inflammatory cytokines It has been observed that reduced levels of IL favor the development of gastrointestinal pathologies such as inflammatory bowel disease Recombinant IL has indeed been effective in the treatment of some of these diseases.
Independent of recycling endosomes, IL was also observed to exit directly from the Golgi to the cell surface in apoE-labeled vesicles Transforming growth factor beta is synthesized as a precursor and is directed to the ER by virtue of its signal peptide.
Cleavage by the endoprotease furin, which can happen at the ER or in the extracellular environment, is required for activation of this cytokine Although the secretory mechanism of this cytokine has not been explored, it is possible that it follows a post-Golgi pathway similar to that of TNF, IL-6, or IL Chemokines are a special family of heparin-binding cytokines that are able to guide cellular migration in a process known as chemotaxis.
Cells that are attracted by chemokines migrate toward the source of that chemokine. During immune surveillance, chemokines play a crucial role in guiding cells of the immune system to where they are needed In the inflammatory response, chemokines are released by a wide variety of cells involved in both innate and adaptive immunity Below is a description of the main chemokines released by macrophages.
Both chemokines are angiogenic and may promote the development of tumors such as melanomas CCL5, or the regulated upon activation normal T cell expressed and secreted RANTES , is an inflammatory chemoattractant for T cells, basophils, eosinophils, and dendritic cells to the site of inflammation Similar to CXCL1 and 2, it promotes tumorigenesis and metastasis CCL5 is synthesized in the ER and traffics to the Golgi complex before being exported outside of the cell.
CXCL8 is a potent chemoattractant for neutrophils, in which it also induces degranulation and morphological changes 78 , Since macrophages are some of the first cells to respond to an antigen, they are likely the first cells to release CXCL8.
Other cells such as keratinocytes, endothelial cells, eosinophils, and basophils also respond to this chemokine. CXCL9, also known as monokine induced by gamma interferon MIG , is a strong T cell chemoattractant to the site of inflammation 71 , It mediates cell recruitment necessary for inflammation and repair of tissue damage.
CXCL9 also inhibits neovascularization 83 and has anti-tumor and anti-metastatic effects CXCL10, or interferon gamma-induced protein 10, is secreted not only by monocytes and macrophages, but also by fibroblasts and endothelial cells It serves to attract T cells, NK cells, dendritic cells 84 , and also has potent anti-cancer activity. It also inhibits angiogenesis and tumor formation Polarization signals may be apoptotic cells, hormones, immune complexes, or cytokines provided by lymphocytes or other cells.
In addition, M1 macrophages secrete high levels of reactive oxygen species ROS and reactive nitrogen species RNS , produce and secrete iNOS, and promote the metabolism of arginine into nitric oxide and citrulline. As a result, M1 macrophages foster a highly microbicidal environment, and have a role in mediating the destruction of pathogens and tumor cells.
M1-derived chemokines help recruit NK and Th1 cells. In stark contrast, exposure or treatment of monocytes with IL-4 and IL polarizes these cells toward an M2a phenotype 8 , Those macrophages express a series of chemokines that promote the accrual of Th2 cells, eosinophils, and basophils.
Through chemokine production, M2b macrophages also promote recruitment of eosinophils and Tregs that foster a Th2 response. They also express high levels of arginase and promote tissue regeneration and angiogenesis 8 , The capacity of M2c macrophages to induce Tregs makes them more effective than M2a macrophages at protecting organs from injury caused by inflammatory infiltrates Macrophage bias is reversible. For example, if an M1 macrophage is given apoptotic cells, it may transform into an M2 macrophage.
Figure 1. Monocytes can become phenotypically distinct macrophages. Upon encountering different stimuli, monocytes turn into highly microbicidal M1 , or into immunosuppressive macrophages M2. Stimuli can range from microbial substances to biochemical signals provided by the microenvironment of a given tissue. Many of the cytokines that bias macrophage phenotype are provided by surrounding lymphocytes or other non-immune cells.
Macrophage subtypes release a vastly different array of cytokines and chemokines that can either promote inflammation and sometimes tissue destruction, or wound healing and tissue repair.
M1 macrophages are known to be tumor suppressive whereas M2 macrophages generally promote tumorigenesis. It is important to note that macrophage bias is a spectrum and is reversible. IC, immune complexes; ApC, apoptotic cells; Gluc, glucocorticoids. The characteristics of M1 and M2 macrophages have implicated them in the development of infectious disease and cancer. For example, helminth-derived molecules can strongly bias macrophages toward an M2 phenotype. Blood vessels will then leak blood into the surrounding tissue, allowing immune cells to travel via the leaked fluid to the damaged area, and start the healing process.
While cytokine production mainly occurs when the body is infected by a pathogen, cytokine-induced inflammatory responses also happen when tissues are physically damaged, such as if you tripped and cut your knee on the sidewalk.
Our immune system can be divided into two categories: the innate immune system and the adaptive immune system.
The innate immune system refers to the immunity that you're born with, which targets general health threats, while adaptive immunity refers to acquired immunity, which targets more specific pathogens. Cytokines are "at the crossroads of bridging the communication between the innate and adaptive immune responses," Ford said.
That's because the amount and type of cytokines that cells secrete differ depending on the type of pathogen, and those differences help the immune system appropriately tailor its response to be innate or adaptive. Certain cytokines can stimulate either the innate immune system, adaptive one, or a mix of both depending on the infection.
Cytokines can also direct brain cells to release chemicals that tell your body that you're sick, prompting you to rest and avoid activities that could further expose you to pathogens.
Related: 11 surprising facts about the immune system. Without cytokines, the innate immune system wouldn't know when to activate because there would be no indication of a threat.
Once activated, innate immune cells don't secrete cytokines intended for any specific receptors at first, Ford said. Rather, secreted cytokines will target the entire body, causing fever, achy joints and fatigue, according to a study published in the journal International Anesthesiology Clinics. The adaptive immune system will eventually secrete specific cytokines that target and activate T-cells in order to fine-tune the immune response toward the specific introduced pathogen, reported a study from The Journal of Allergy and Clinical Immunology.
Cytokines signal the adaptive immune system to activate when the innate immune system fails to subdue an infection. While the innate immune system is good at warding off general health threats, it may fail to destroy foreign pathogens.
Cytokines direct the adaptive immune system to produce pathogen-specific antigens that quickly identify the pathogen so the immune system can destroy it. Register Log in.
Cytokines: Introduction Download cytokines - introduction. Download Cytokines - Introduction. Figure 1. Cytokine mode of action, with specific examples. Bitesize category Receptors and Molecules. Related Articles Cytokines: Introduction. Chemokines: Introduction. Chemokine receptors on monocytes.
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