Monocytes- Definition, Structure, Immunity, Subsets, Functions

Monocytes are a type of white blood cell that play a vital role in the immune system. They are involved in both the innate and adaptive immunity, which are the two main branches of the body`s defense against infections and diseases. Innate immunity is the first line of defense that responds quickly and nonspecifically to any foreign invaders, while adaptive immunity is the second line of defense that develops a specific and long-lasting response to a particular pathogen.

Monocytes are produced in the bone marrow from a common progenitor cell called the common myeloid progenitor (CMP). They circulate in the blood for about three days before they migrate into tissues and differentiate into different types of cells, such as macrophages and dendritic cells. Macrophages are large phagocytic cells that engulf and destroy microbes, dead cells, and debris. Dendritic cells are antigen-presenting cells that capture and process antigens and present them to T cells, which are another type of white blood cell that mediate adaptive immunity.

Monocytes are not only important for fighting infections, but also for maintaining homeostasis, tissue repair, wound healing, inflammation, and immune regulation. They can also respond to various signals and stimuli from the environment and change their phenotype and function accordingly. For example, they can differentiate into osteoclasts, which are cells that break down bone tissue, or into foam cells, which are cells that accumulate cholesterol and contribute to atherosclerosis.

Monocytes are heterogeneous and can be classified into different subsets based on their surface markers, size, shape, function, and location. The most common way to distinguish monocytes is by their expression of CD14 and CD16, which are two receptors that bind to different molecules on pathogens or host cells. CD14+ monocytes are the classical or conventional monocytes that make up about 80-90% of the circulating monocytes. They are larger and more phagocytic than CD16+ monocytes, which are the non-classical or proinflammatory monocytes that make up about 10% of the circulating monocytes. CD16+ monocytes produce more inflammatory cytokines and have a higher capacity to migrate into tissues. There is also a third subset of monocytes called CD14+CD16+ transitional monocytes, which are intermediate between the other two subsets and have a high potential to differentiate into dendritic cells.

In this article, we will explore the definition, structure, immunity, subsets, and functions of monocytes in more detail. We will also discuss how monocytes interact with other cells and molecules of the immune system and how they contribute to health and disease.

Monocytes are a type of white blood cell that belong to the myeloid lineage of the hematopoietic system. They are produced in the bone marrow from common myeloid progenitor cells and then released into the bloodstream, where they circulate for about three days before migrating into tissues. Monocytes are part of the innate immune system and play a crucial role in defending the body against various pathogens and foreign substances. They can also differentiate into macrophages and dendritic cells, which are specialized cells that modulate the adaptive immune system.

Monocytes are characterized by their large size (14-20 µm in diameter), irregular shape, oval or kidney-shaped nucleus, and abundant cytoplasm with granules and vesicles. They have various receptors on their surface that allow them to recognize and respond to different stimuli, such as toll-like receptors (TLRs), chemokine receptors, immunoglobulin receptors, adhesion molecules, and scavenger receptors. Depending on the expression of these receptors, monocytes can be classified into different subsets that have distinct functions and phenotypes.

The main subsets of monocytes in humans are:

• CD14highCD16– monocytes, also known as classical or inflammatory monocytes. They account for about 80-90% of the total circulating monocytes and are involved in phagocytosis, inflammation, and tissue repair. They express high levels of CD14, a component of the lipopolysaccharide (LPS) receptor complex, and low or no levels of CD16, a low-affinity immunoglobulin G (IgG) receptor.
• CD16highCD14– monocytes, also known as non-classical or patrolling monocytes. They account for about 10% of the total circulating monocytes and are involved in surveillance, antigen presentation, and cytokine production. They express high levels of CD16 and low or no levels of CD14.
• CD14+CD16+CD64+ monocytes, also known as intermediate or transitional monocytes. They account for a small fraction of the total circulating monocytes and are involved in phagocytosis, antigen presentation, and T cell activation. They express intermediate levels of CD14 and CD16 and high levels of CD64, a high-affinity IgG receptor.

Monocytes are essential for both innate and adaptive immunity as they can perform various functions depending on the context and stimuli. Some of these functions are:

• Phagocytosis: Monocytes can engulf and destroy microorganisms, antigens, and dead or damaged cells by using their cytoplasmic granules and vesicles that contain enzymes and reactive oxygen species (ROS).
• Antigen presentation: Monocytes can process and present antigens to other immune cells, such as T cells and B cells, by using their major histocompatibility complex (MHC) class II molecules and co-stimulatory molecules.
• Cytokine production: Monocytes can secrete various cytokines that regulate inflammation, immune response, cell differentiation, and tissue repair. Some examples of cytokines produced by monocytes are tumor necrosis factor (TNF), interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-12 (IL-12), and interferon-gamma (IFN-gamma).
• Differentiation: Monocytes can differentiate into macrophages and dendritic cells in response to different signals and stimuli. Macrophages are tissue-resident phagocytic cells that have a variety of functions depending on their location and activation state. Dendritic cells are antigen-presenting cells that capture antigens from the environment and migrate to lymph nodes to activate T cells.

Monocytes are vital for maintaining homeostasis and protecting the body from infections and diseases. However, dysregulation or dysfunction of monocytes can also contribute to pathological conditions such as chronic inflammation, autoimmune disorders, cancer, sepsis, atherosclerosis, and neurodegeneration. Therefore, understanding the biology of monocytes is important for developing novel therapeutic strategies for these conditions.

Monocytes are a type of white blood cell (leukocyte) that play an important part in the immune system`s ability to destroy invaders like viruses, bacteria, and fungi. Monocytes form in the bone marrow and are released into the blood. They can also help support the removal of infected cells and aid in healing and repair of the body.

Monocytes are essential for both the innate immune system and the adaptive immune system as these differentiate into macrophages and dendritic cells. Monocytes are one of the master cells of the immune system as these can perform a group of different functions performed by different immune cells.

These can recognize danger signals or stimuli via their pattern recognition receptors, resulting in phagocytosis. These can also present antigens to other cells and secrete chemokine and cytokines.

Monocytes are considered cells of the innate immune system as these are involved in responses against viral, bacterial, fungal, or parasitic infections. These are mononuclear phagocytic cells of the immune system, which are described by different morphological and physiological characteristics depending on the stage of differentiation of the cells.

Monocytes have toll-like receptors on the cell membrane, which can interact with pathogen-associated molecular patterns (PAMPs) that occur in invading pathogens. The binding produces a signal which causes monocytes to migrate from the bone marrow to the peripheral blood circulation within 12 to 24 hours.

In order to enter the affected areas, monocytes should first bind to the endothelium and then move through the vascular surface. Finally, the monocytes adhere to the endothelium and finally make their way through the endothelial cells by the process of diapedesis. The monocytes can then penetrate the endothelial basement membrane and migrate to the area of inflammation.

The differentiation of monocytes occurs at the site of inflammation, and the differentiation depends on the growth factors and cytokines produced during the process. Monocytes in the area of inflammation can also act as phagocytic cells that engulf microorganisms, foreign materials, and dead and damaged cells.

Some monocytes release cytokines, which helps in the recruitment of other cells and compounds into the affected area and induce further inflammation.

Monocytes also influence adaptive immune responses by differentiating into dendritic cells, which are antigen-presenting cells that activate T cells and B cells. Monocytes can also differentiate into macrophages, which are long-lived phagocytic cells that can kill intracellular pathogens and regulate tissue homeostasis.

Monocytes are highly plastic and heterogenous as these can change their functional phenotypes depending on the environmental stimuli. Monocytes can be divided into different subsets based on their expression of surface markers such as CD14 and CD16. These subsets have distinct roles in inflammation, tissue repair, angiogenesis, and immunity.

Monocytes are indispensable leukocyte subsets of the innate immune system that play a major role in defending the host from invading pathogens. They also bridge innate and adaptive immunity by differentiating into various cell types that modulate immune responses and tissue functions.

Monocytes are the largest cells in the peripheral blood, with a diameter ranging from 12 to 22 µm . They have an irregular cell shape and a high nucleus-to-cytoplasm ratio (about 3:1). The nucleus is prominent and often indented, folded, or bilobed, giving the monocyte a bean-shaped or kidney-shaped appearance . The nucleus contains a chromatin net with strands bridging tiny clumps of chromatin that are arranged on the inner side of the nuclear membrane.

The cytoplasm of monocytes is light basophilic or blue-gray in color and contains granules, vesicles, and sometimes vacuoles . The granules are small (0.05 to 0.2 µm in diameter), dense, homogenous, and have a limiting membrane. The vesicles are larger (0.5 to 1 µm in diameter) and contain various substances such as enzymes, cytokines, or antigens. The vacuoles are formed by phagocytosis of foreign particles or cellular debris and can occupy a large part of the cytoplasm.

The surface of monocytes has ruffles and blebs that are involved in cell motility and adhesion . The cell membrane also has numerous microvilli that extend into the surrounding plasma and help in locomotion and adherence to other cells. The cell membrane also expresses various receptors that enable monocytes to recognize and respond to different stimuli. Some of these receptors are:

• CD14: A component of the lipopolysaccharide receptor complex that binds to bacterial endotoxins.
• CD16: A low-affinity receptor for immunoglobulin G (IgG) that mediates antibody-dependent cellular cytotoxicity.
• CD64: A high-affinity receptor for IgG that enhances phagocytosis and antigen presentation.
• Toll-like receptors (TLRs): A family of receptors that recognize pathogen-associated molecular patterns (PAMPs) and initiate inflammatory responses.
• Chemokine receptors: Receptors that bind to chemokines, which are small proteins that attract and activate leukocytes.
• Scavenger receptors: Receptors that bind to modified low-density lipoproteins (LDLs), oxidized phospholipids, apoptotic cells, and other ligands that are associated with tissue damage or infection.

Monocytes can leave the blood and differentiate into macrophages or dendritic cells in various tissues, depending on the local signals and stimuli. These differentiated cells have different structures and functions that will be discussed in the next sections.

Monocytes are a heterogeneous group of cells that can be classified into different subsets based on their surface markers, gene expression profiles, and functional properties. In humans, three circulating monocyte subsets are recognized:

• Classical monocytes (CD14++CD16−): These are the most abundant monocyte subset in the blood, accounting for about 80-90% of the total monocytes. They are characterized by high expression of CD14, a co-receptor for lipopolysaccharide (LPS), and low or absent expression of CD16, a low-affinity receptor for immunoglobulin G (IgG). Classical monocytes are involved in phagocytosis, antigen presentation, and cytokine production. They can differentiate into macrophages and dendritic cells upon stimulation by inflammatory signals or tissue damage.

• Non-classical monocytes (CD14+CD16++): These are the smallest and least abundant monocyte subset in the blood, representing about 10% of the total monocytes. They express low levels of CD14 and high levels of CD16, which confer them enhanced responsiveness to IgG-opsonized pathogens and apoptotic cells. Non-classical monocytes are also known as pro-inflammatory monocytes, as they produce high levels of tumor necrosis factor (TNF) and low levels of interleukin-10 (IL-10) upon activation by toll-like receptors (TLRs). They play a role in tissue surveillance, wound healing, and angiogenesis. They can also differentiate into macrophages and dendritic cells under certain conditions.

• Intermediate monocytes (CD14++CD16+): These are a transitional subset of monocytes that express high levels of both CD14 and CD16. They account for about 5-10% of the total monocytes in the blood. They have intermediate characteristics between classical and non-classical monocytes, such as phagocytic activity, cytokine production, and antigen presentation. They also express high levels of major histocompatibility complex (MHC) class II molecules and other co-stimulatory molecules, which enable them to activate T cells. Intermediate monocytes are considered highly plastic and responsive to environmental cues.

The classification of monocyte subsets is based on the relative expression levels of CD14 and CD16, which are not exclusive markers for monocytes. Therefore, other surface molecules have been used to further define the phenotypic and functional diversity of monocyte subsets. For example, slan (6-sulfo LacNAc) is a specific marker for non-classical monocytes that can distinguish them from intermediate monocytes. Other markers that have been used to identify monocyte subsets include CD64, CCR2, CX3CR1, HLA-DR, CD11b, CD11c, CD36, CD163, and CD206.

The distribution and function of monocyte subsets may vary depending on the physiological or pathological conditions. For instance, during inflammation or infection, the number of circulating classical monocytes increases, while the number of non-classical monocytes decreases. This is due to the recruitment of classical monocytes to the inflamed tissues and the retention of non-classical monocytes in the vascular endothelium. Moreover, different subsets of monocytes may have distinct roles in different diseases, such as obesity, atherosclerosis, chronic obstructive pulmonary disease (COPD), lung fibrosis, lung cancer, and Alzheimer`s disease. Therefore, understanding the heterogeneity and plasticity of monocyte subsets is important for developing novel therapeutic strategies for these diseases.

Monocytes are one of the key players in the immune system, as they can perform various functions to protect the body from different types of pathogens. Monocytes can act as:

• Phagocytes that engulf and destroy microbes and foreign particles
• Antigen-presenting cells that process and present antigens to T cells and B cells
• Cytokine producers that secrete inflammatory mediators and modulate immune responses
• Precursors of macrophages and dendritic cells that differentiate into tissue-resident cells with specialized functions

Phagocytosis

Monocytes have toll-like receptors (TLRs) on their surface, which can recognize pathogen-associated molecular patterns (PAMPs) that are present on the surface of microbes. When monocytes encounter a pathogen, they bind to it via their TLRs and initiate a signaling cascade that leads to the activation of the monocyte. The activated monocyte then engulfs the pathogen by extending its plasma membrane around it and forming a phagosome. The phagosome then fuses with a lysosome, which contains digestive enzymes and reactive oxygen species that kill and degrade the pathogen. The monocyte can also release some of the digested material to the extracellular space, where it can be recognized by other immune cells .

Antigen presentation

Monocytes can also act as antigen-presenting cells (APCs), which are essential for the activation of the adaptive immune system. Monocytes can process the antigens derived from the phagocytosed pathogens and present them on their surface in association with major histocompatibility complex (MHC) molecules. MHC molecules are proteins that display antigens to T cells and B cells, which are lymphocytes that mediate specific immune responses. Monocytes can express both MHC class I and MHC class II molecules, which present antigens to different types of T cells. MHC class I molecules present antigens to CD8+ T cells, which are cytotoxic T cells that can kill infected cells. MHC class II molecules present antigens to CD4+ T cells, which are helper T cells that can secrete cytokines and stimulate other immune cells .

Cytokine production

Monocytes can also produce various cytokines, which are signaling molecules that regulate immune responses. Cytokines can have different effects depending on the type, concentration, and target cell of the cytokine. Some cytokines can promote inflammation, which is a protective response that aims to eliminate pathogens and repair tissue damage. Some cytokines can suppress inflammation, which is necessary to prevent excessive tissue damage and restore homeostasis. Some cytokines can also modulate the differentiation and function of other immune cells, such as macrophages, dendritic cells, T cells, and B cells .

Some examples of cytokines produced by monocytes are:

• Interleukin-1 beta (IL-1β): A pro-inflammatory cytokine that induces fever, stimulates acute phase proteins, and activates endothelial cells
• Interleukin-6 (IL-6): A pro-inflammatory cytokine that induces fever, stimulates acute phase proteins, and promotes B cell differentiation
• Interleukin-10 (IL-10): An anti-inflammatory cytokine that inhibits the production of pro-inflammatory cytokines and enhances tissue repair
• Interleukin-12 (IL-12): A cytokine that stimulates the differentiation of naive T cells into Th1 cells, which are helper T cells that enhance cellular immunity
• Tumor necrosis factor alpha (TNF-α): A pro-inflammatory cytokine that induces apoptosis, activates endothelial cells, and stimulates chemokine production

Differentiation

Monocytes can also differentiate into macrophages and dendritic cells, which are tissue-resident cells with specialized functions. Macrophages are phagocytic cells that reside in various tissues and organs, where they perform tissue-specific roles such as wound healing, tissue remodeling, antigen presentation, and cytokine production. Dendritic cells are antigen-presenting cells that reside in peripheral tissues and lymphoid organs, where they capture antigens from the environment and migrate to lymph nodes to activate naive T cells .

The differentiation of monocytes into macrophages and dendritic cells depends on various factors, such as:

• The type of monocyte: Classical monocytes (CD14highCD16-) tend to differentiate into macrophages, while non-classical monocytes (CD14lowCD16+) and intermediate monocytes (CD14+CD16+) tend to differentiate into dendritic cells
• The tissue microenvironment: Different tissues secrete different growth factors and cytokines that influence the differentiation of monocytes. For example, granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) promote the differentiation of monocytes into dendritic cells, while macrophage colony-stimulating factor (M-CSF) and interferon-gamma (IFN-γ) promote the differentiation of monocytes into macrophages
• The type of pathogen: Different pathogens can trigger different signaling pathways in monocytes that affect their differentiation. For example, lipopolysaccharide (LPS), a component of gram-negative bacteria, induces the differentiation of monocytes into inflammatory macrophages, while zymosan, a component of fungi, induces the differentiation of monocytes into anti-inflammatory macrophages

Monocytes are one of the most versatile and multifunctional cells of the immune system. They perform a variety of roles in homeostasis, infection, inflammation, and tissue repair. Some of the main functions of monocytes are:

• Phagocytosis: Monocytes can engulf and destroy microorganisms, foreign particles, dead or damaged cells, and cancer cells by a process called phagocytosis . They use their toll-like receptors (TLRs) to recognize and bind to pathogen-associated molecular patterns (PAMPs) on the surface of the invaders. They also secrete enzymes and reactive oxygen species (ROS) to kill the ingested microbes.
• Antigen presentation: Monocytes can also act as antigen-presenting cells (APCs) that process and present antigens to other immune cells, especially T cells . They use their major histocompatibility complex (MHC) molecules to display the antigen fragments on their surface. They also secrete cytokines and chemokines to activate and recruit other immune cells.
• Cytokine production: Monocytes produce a range of cytokines that modulate the immune response and inflammation. Cytokines are small proteins that act as messengers between cells. Depending on the type and context of stimulation, monocytes can produce pro-inflammatory cytokines (such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), interleukin-12 (IL-12), etc.) or anti-inflammatory cytokines (such as interleukin-10 (IL-10), transforming growth factor-beta (TGF-β), etc.) .
• Differentiation: Monocytes can differentiate into various cell types depending on the environmental cues and signals. They can give rise to tissue macrophages and dendritic cells, which are involved in phagocytosis, antigen presentation, cytokine production, wound healing, and tissue remodeling . They can also differentiate into osteoclasts, which are involved in bone resorption and remodeling. Furthermore, monocytes can differentiate into foam cells, which are involved in atherosclerosis and lipid metabolism.

Monocytes are essential for both innate and adaptive immunity as they can sense, respond, and adapt to various stimuli and challenges. They are also involved in maintaining tissue homeostasis and repairing tissue damage. However, dysregulation of monocyte function can also contribute to various diseases such as infections, autoimmune disorders, chronic inflammation, cancer, etc.

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