Granulocytes

Definition, Types, Function and Role as Phagocytes 


Definition: What are Granulocytes?




Also known as polymorphonuclear leukocytes, granulocytes, which are the most abundant immune cells, are components of the innate (but also play a part in adaptive immunity) immune system that are characterized by cytoplasmic granules.

As a subset of white blood cells (leucocytes) and the first line of defense, granulocytes play an important role in defending the body against pathogens as rapid responders.

Based on new studies, the plasticity and diversity of these cells allow them to play a number of other important roles in immunity. 

* Granulocytes make up between 50 and 70 percent of the total white blood cells.

Types of granulocytes:



Characteristics of Neutrophils


One type of granulocyte, known as polymorphonuclear neutrophils or simply neutrophils make up the majority of leukocytes in humans and mice. However, they are the smallest of the three granulocytes.

Like the other granulocytes, neutrophils contain numerous granules that contain the microbicidal agents. Apart from the primary granules, they also contain secondary granules that contain several types of enzymes. 

The nucleus, which is multi-lobed, consists of between 3 and 5 lobes that join to each other by thin strands of genetic material.


Some of the other characteristics of neutrophils include:

  • With regards to size, they range between 9 and 15um in diameter
  • Use amoeboid motion for locomotion 
  • In the bone marrow, it takes about 7 days to form a mature neutrophil cell
  • Movement in any direction is dependent on the concentration gradient of various substances (chemotaxis)
  • Destroy foreign microorganisms through phagocytosis


Production and Functions


Neutrophils, described as privates of the innate immune system in some books, are produced in the bone marrow. Here, in a process regulated by cytokine granulocyte colony-stimulating factor, neutrophils develop from the proliferation and maturation of progenitor and precursor cells.


This process may be represented as follows:

Progenitor cells →myeloblast→promyelocyte→myelocyte→metamyelocyte→band neutrophil→segmented neutrophil

* While the early progenitor cells cannot be readily identified under the microscope, myeloblasts and consequent cells that ultimately give rise to mature neutrophils can be differentiated based on their morphological characteristics.

Under normal conditions (in a healthy individual), about 1011 neutrophils are released from the bone marrow on a daily basis. This number, however, changes with stressful immunological conditions.

Under normal conditions, these cells have a short half-life of a few hours outside the bone marrow (in the blood). Five to six hours after being released into the bloodstream, neutrophils are phagocytosed and destroyed in the spleen and liver. For the most part, they are destroyed/cleared at the same rate they were produced which allows a relatively constant number in circulation at all times. 

* Some neutrophils are retained in the bone marrow where they form the bone marrow reserve. In the event of an infection, neutrophils are released in high numbers in a process regulated by chemokines and cytokines. 


* The reserve pool (number of neutrophils retained in the bone marrow) consists of about 20 times the number of neutrophils in circulation.



Mobilization


As a physical barrier, the skin plays an important role in not only protecting the internal tissues and organs from external mechanical forces, but also from various microorganisms. This is also enhanced by mucous membranes that trap these organisms and prevent them from gaining entrance into the body. However, when microorganisms overcome these barriers, neutrophils are mobilized to respond to the infection. 

According to studies conducted on mice, the presence of microbes was shown to result in the production of cytokines which stimulated granulopoiesis. In the event of an infection, neutrophils have also been shown to produce Pre-B cell colony-enhancing factor - molecules that prohibit apoptosis of neutrophils. 

* Activated neutrophils have to travel from the bloodstream to the site of infection.


This process (recruitment) occurs through three main phases that include:

  • Initiated adherence to activated endothelial cells
  • Attachment of neutrophils to the endothelium (known as neutrophil arrest) 
  • Migration across the endothelium to the infected site  

At the site of infection, foreign microorganisms (e.g. bacteria) are taken up through phagocytosis and destroyed in the vacuole by a range of bactericidal substances.

The engulfing action of neutrophils results in the formation of vacuoles known as phagosomes. This vacuole then fuses with the lysosome to form a cytoplasmic body known as phagolysosome that contains such proteolytic enzymes as lysozyme among other molecules that serve to destroy the engulfed pathogen. This process also results in the production of molecules that stimulate the production and recruitment of more neutrophils. 

Apart from phagocytosis, neutrophils have also been shown to destroy bacteria using extracellular traps. Following the entry of bacteria, neutrophils produce mesh-like structures that consist of histones and various antimicrobial substances.

The entrapment of pathogens in the mesh allows antimicrobial substances to destroy them and prevent further infection. According to studies, this action is promoted by the production of reactive oxygen species produced during phagocytosis.

While the mesh-like structures play an important role in trapping and killing pathogens, they have also been associated with an inflammatory disease where ligands are deposited to various components of tissues. For instance, poor control of the mesh-like structures has been associated with vasculitis, sepsis as well as nephritis. 

* The proteins produced by neutrophils also tend to cause tissue damage (affecting healthy cells). To prevent further damage, a number of negative feedback loops during various stages of immune response (by neutrophils) ultimately deactivate the neutrophils.



Eosinophils



The Granulocytes called Eosinophils are characterized by a bi-lobed nucleus and large cytoplasmic granules that contain various enzymes and proteins. Although they are short-lived in circulating blood, they last longer in tissue (a few days to 2 weeks). As compared to neutrophils, eosinophils are larger, measuring between 8 and 12um in diameter.

Unlike neutrophils, which make up at least 50 percent of the total white blood cells, eosinophils only make up between 0.5 to 6 percent of all nucleated cells produced in the bone marrow.

They play a crucial role in body immunity and are therefore routinely measured as part of the full blood cell count. While they are part of the innate immune system, they're also involved in the adaptive immune system. Although they play an important role in defending the body against parasitic infections like neutrophils, eosinophils are also involved in hypersensitivity reaction (allergic reactions).

* Unlike neutrophils, eosinophils are less effective when it comes to killing bacteria through phagocytosis.


* Eosinophils also protect the body against parasitic infections.



Production


Like neutrophils, eosinophils are also produced in the bone marrow. Here, committed multipotent progenitors develop along a given lineage to give rise to mature eosinophils.


This may be represented as follows:

Multipotent hematopoietic stem cells → myeloid lineage → myeloblast→ eosinophil

* The development of mature eosinophils from hematopoietic stem cells in the bone marrow is controlled by such transcription factors as the Δdbl-GATA-1and cytokines (e.g. IL-3)


* As is the case with neutrophils, the development of eosinophils to maturity in the bone marrow takes about a week.

According to research studies, the last phase of eosinophils development is influenced by Interleukin-5 (IL-5 is produced by such cells as CD34+, Th2 lymphocytes, mast cells etc) which is essential for their differentiation and survival. Moreover, the cytokines have also been shown to play a role in promoting the migration of the cells from the bone marrow to blood (circulating blood).

In the event of an infection, however, it is the chemokines that promote the recruitment of these cells. Here, such chemokine receptors as CCR3 bind to the eotaxins (eosinophil chemotactic proteins) and various stimuli of inflammation which promotes the recruitment of eosinophils to the affected tissue. 

* Once they are released from the bone marrow, eosinophils can migrate and settle in various tissues/organs where they reside for several days (to about 2 weeks).

In the event of an infection, eosinophils migrate to given tissues (affected sites) through the lymphatic channels. Here, some of the substances that have been shown to promote this migration include eotaxins, anaphylatoxins, and IL5 among others.

On the other hand, T lymphocytes and mast cells are involved in the recruitment of eosinophils to the affected site. Like neutrophils, then, eosinophilic actions are largely dependent on chemotactic signals.

Based on medical studies that focused on asthmatic children, eosinophils were also shown to be actively motile by emoting pseudopods. 

* Eosinophils are phagocytic and destroy various microorganisms through phagocytosis.


Unlike neutrophil granules, the granules of eosinophils contain galectin-10 (hydrophobic proteins) that contributes to the formation of Charcot-Leyden crystals in the tissue and biological fluids of patients suffering from eosinophil inflammation.

Contents of these granules, however, have been shown to be toxic to parasites and thus allow eosinophils to protect the body against various parasites. 

Apart from killing foreign microorganisms through phagocytosis, eosinophils also play a role in T cell activation. Eosinophils achieve this by presenting antigens to the CD4+ T cells.

Based on a number of other studies, these cells have also been shown to be capable of processing and presenting a number of other organisms including viruses, superantigens, and various parasitic antigens. In doing so, eosinophils contribute to the activation and proliferation of T cells thus contributing to the functions of other cells. 

* Eosinophils also play a role in T cell polarization.


* Like neutrophils, eosinophils also produce extracellular traps consisting of DNA that trap and contribute to the destruction of various microorganisms. 


Some of the other functions of eosinophils include:

· Mast cell regulation - Through the release of various proteins and cytokines, eosinophils regulate the activation and production of mast cells. At the same time, mast cells are also involved in the activation of eosinophils. 

 

· Promote maturation and homing of various immune cells - In such organs as the spleen, thymus and the gut etc, eosinophils have been shown to contribute in the maturation and homing of a number of immune cells. 

 

· Promote plasma cell survival - Eosinophils contribute to the survival of the plasma cell in the bone marrow as well as in the gut, Here, they also play a role in maintaining a physiological balance between the T-helper and T-regulatory responses. 

 

  • Essential for the proper development of mammary glands
  • Contribute to the functional properties of nonlymphoid organs
  • Contribute to tissue repair through the production of a number of growth factors 



Basophil Characteristics


Discovered in 1879 by Paul Ehrlich, basophils are a type of granulocyte that make up about 1 percent of the total human leukocytes. They share functional similarities with mast cells and share several characteristics with the other granulocytes.

In addition to providing defense against various microscopic pathogens, basophils also respond to attacks by ticks and filarial worms. They are also involved in allergic disease by releasing various cytokines and mediators that contribute to given hypersensitivity reactions.



Basophils are characterized by a bi-lobed nucleus and range between 12 and 17um in diameter in size. Because of the high number of the granules (which appear purple in color following staining) the nucleus cannot be easily identified/seen under the microscope.

Because the phagocytic action of basophils is very mild, immune functions are largely achieved through degranulation. This allows for a variety of substances to be released into the environment to act against invading microorganisms and other organisms. 


Production


Like the other granulocytes, basophils are produced in the bone marrow (from progenitor known as Lin-CD34+FcεRIhic-Kit- cells). Here, basophils develop and mature before being released into the periphery under the control of C/EBPα which acts as the transcription factor.

While the mechanism through which stimuli promote basophil development during parasitic infections is yet to be well understood, in vitro studies found hematopoietic cytokine IL-3 to contribute in the differentiation of the granulocytes. Such molecules as proteases, glycoproteins and a number of other structural components of parasites have been shown to stimulate the production of cytokines and the consequent recruitment of basophils to the affected sites. 

In the event of an allergic inflammation or an infection, basophils are stimulated and leave the periphery as they migrate to the affected sites. Here, cell migration (basophil cells) entails adhering to the endothelium, transendothelial migration as well as locomotion to the affected site. While they destroy various microorganisms through phagocytosis, this activity has been shown to be mild. 

Although they have a very mild phagocytic function, basophils play a predominant role in allergic reactions. This is achieved through the release of a number of substances including histamine, bradykinin, serotonin, as well as anaphylaxis. Here, the release of these substances results in various vascular and tissue reactions that cause allergic manifestations. 

* Through the release of eosinophil chemotactic factors, basophils also prevent the spread of further allergic inflammatory processes. Here, eosinophils are stimulated to migrate to the affected tissue where they destroy antigen-antibody complexes through phagocytosis.

Release of heparin is also an important role of basophil. This prevents the clotting of blood. In blood, heparin also stimulates and actives the enzyme lipoprotein lipase that serves to remove fat particles in blood which also helps prevent clotting. 



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References


Booki Min and William E. Paul. (2012). Basophils and Type 2 Immunity. ncbi.

C. Wayne Smith. (2012). Chapter 61: Production, Distribution, and Fate of Neutrophils. Access Medicine. 

Giuseppe A. Ramirez. (2017). Eosinophils from Physiology to Disease: A Comprehensive Review. BioMed Research International Volume 2018, Article ID 9095275, 28 pages.

Rebecca C Furze and Sara M Rankin. (2008). Neutrophil mobilization and clearance in the bone marrow. NCBI.

Tie-Shan Teng, Ai-ling Ji, Xin-Ying Ji, and Yan-Zhang Li. (2016). Neutrophils and Immunity: From Bactericidal Action to Being Conquered. Journal of Immunology Research Volume 2017, Article ID 9671604, 14 pages.

Links


https://www.immunology.org/public-information/bitesized-immunology/cells/neutrophils

https://www.britannica.com/science/neutrophil


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