Cell of the Month: Mast Cells

May 27, 2024 | Disease Models

Mast cells are tissue-resident immune cells derived from the myeloid lineage, and along with basophils, eosinophils and neutrophils, they belong to the granulocyte family of white blood cells. 

First discovered and named almost 200 years ago by German pathologist Friedrich Daniel von Recklinghausen and German physician and scientist Paul Ehrlich, mast cells have diverse functions in innate and adaptive immunity, including a major role in allergy and anaphylaxis, as well as inflammation, immune tolerance, tissue repair and angiogenesis, defense against toxins and parasites, and others. With the exception of the brain and the retina, mature mast cells occupy connective tissues in every organ throughout the body (1).

In this article, we provide a brief introduction to mast cell origins and morphology, and summarize how they are activated during IgE-mediated allergic responses. 

Origin and destinations of mast cells

Mast cell progenitors originate from the pluripotent progenitor cells of the bone marrow, blood, and yolk sac. Progenitor and mature mast cells express the stem cell factor (SCF) receptor CD117/c-kit throughout their lifetime. Progenitor mast cells undergo maturation in response to the c-kit ligand/STF in the presence of certain growth factors and cytokines produced in the microenvironment of the tissue where they will eventually reside. This property makes them unique among hematopoietic cells, which typically undergo maturation within lymphoid organs or in the bloodstream.

Binding of α4β7 integrins expressed on immature mast cells to the adhesion molecule VCAM-1, which is expressed by the endothelium, triggers the exit of immature mast cells from the circulation. Their subsequent migration to their final destination is governed by the coordinated efforts of integrins, adhesion molecules, chemokines, cytokines, and growth factors, as well as the expression of distinct molecules on the immature mast cell surface. For instance, CXCR2 expression on mast cell progenitors will direct their migration to the small intestine, where mast cells are highly abundant.

Mature mast cells occupy tissues adjacent to blood vessels and close to epithelial surfaces, e.g., in the gastrointestinal tract and the respiratory epithelium, creating a physical barrier for pathogens. Mast cells also occupy areas below the epithelium in connective tissue surrounding blood cells, smooth muscle, mucous, and hair follicles. Because of their location, mast cells are one of the first immune cell types to interact with environmental antigens, environmentally-derived toxins, or invading pathogens.

Mast cell morphology and phenotypic plasticity

Morphologically, mast cells are oval- or irregularly-shaped, containing a single round nucleus. The plasma membrane is decorated with high-affinity IgE receptors (FcεR1) that bind the Fc region of circulating IgE antibodies to trigger the initiation of an IgE-dependent or Type I allergic reaction. This major role of mast cells occurs when IgE is produced by mature B cells upon interaction with  CD4+ Th2-modulated cytokines such as IL-4.

Mast cells contain up to 200 small secretory granules that typically range in size from 0.2 to 0.8 micrometers. These lysosome-like granules are visible as a dense granular cytoplasm under a light microscope, and contain a diverse repertoire of inflammatory mediators, including histamine, heparin, hydrolases, amines, cytokines, proteases and proteoglycans, as well as reactive oxygen species (ROS). Upon mast cell activation, e.g., during an allergic reaction, degranulation occurs, releasing the contents of the granules to the cell exterior, triggering a powerful inflammatory reaction. 

Mast cells are very diverse and the phenotypes and morphologies they exhibit are highly dependent upon the processes they are involved in as well as their local environment. In addition, the abundance of mast cells and their tissue distribution within the body can change during Th2 cell responses and in response to persistent inflammation and/or tissue remodeling. 

While much effort has gone into characterizing the phenotypes of murine and human mast cells, for example based on their protease expression and expansion patterns, no consensus exists among researchers in this area and it has become clear that findings from rodents are not recapitulated in humans (2). This also means that studies using rodents as a model for humans are greatly limited by species differences, and despite decades of research in this area our picture of human mast cell activation and how these cells carry out their diverse roles remains incomplete. 

How are mast cells activated during IgE-mediated allergy? 

As mentioned above, much of what has been published about mast cell biology is based on studies in animals or immortalized cell lines that do not recapitulate the in vivo situation in humans. For this reason, we will not attempt to provide a detailed summary of what might be happening in human mast cells, but instead focus on what has been established with regards to IgE-dependent human mast cell activation, which is by far the most widely-documented role for mast cells in humans. 

The most common physiological route to mast cell activation is IgE-dependent, and this occurs via cross-linking between antigens, IgE, and FcϵRI. Most of the IgE molecules in the human body are bound to the FcϵRI receptors on mast cells. When an antigen (e.g., pollen, dust mites, insect venom, food proteins or certain drugs) comes into contact with a mast cell, it cross-links several of the FcϵRI receptors present on the cell surface. This in turn triggers various kinase signaling cascades, culminating in an increase in the concentration of free Ca2+ in the cytosol. This mobilization of calcium is necessary for the degranulation process, during which histamine, proteases, proteoglycans  and other inflammatory mediators such as TNF-α and certain cytokines are released. 

Lipid-based pro-inflammatory mediators including leukotrienes, prostaglandins and platelet-activating factor are also synthesized during mast cell activation from arachidonic acid that becomes available following the enzymatic activity of phospholipase A2.

All of the above leads to the immediate symptoms of allergy, such as sneezing, itching, hives and allergic asthma. For reasons that are not fully understood – although elevated serum tryptase levels are implicated – mast cell activation sometimes leads to a severe and potentially fatal systemic allergic response known as anaphylaxis.

Although beyond the scope of this article, IgE-independent routes to mast cell activation have been demonstrated in experimental animals and are backed up by clinical observations in humans. In brief (reviewed in 3), these include binding of the complement-derived peptides C3a and C5a to their receptors on mast cells and direct activation of mast cells by drugs that interact with certain receptors on the mast cell surface.

Do mast cells have overlapping functions with other cell types?

Although distinct from macrophages and microglia, researchers are beginning to unravel the significance of crosstalk between these cell types within the tissues they co-reside. In addition, mast cells and macrophages have partially overlapping functions within tissue homeostasis, repair, remodeling and defense, and several features are shared by all three cell types; they are heterogeneous, can activate T cells, and produce many of the same inflammatory mediators. 

Stay tuned for a future article for more on this topic!

References

  1. da Silva EZ, Jamur MC, Oliver C. Mast cell function: a new vision of an old cell. J Histochem Cytochem (2014) 62(10):698–738. doi:10.1369/0022155414545334
  2. Galli SJ, Gaudenzio N, Tsai M. Mast Cells in Inflammation and Disease: Recent Progress and Ongoing Concerns. Annu Rev Immunol. 2020 Apr 26;38:49-77. 10.1146/annurev-immunol-071719-094903. PMID: 32340580.
  3. Finkelman FD, Khodoun MV, Strait R. Human IgE-independent systemic anaphylaxis. J Allergy Clin Immunol. 2016 Jun;137(6):1674-1680.

Karen O’Hanlon Cohrt is an independent Science Writer with a PhD in biotechnology from Maynooth University, Ireland (2011). After her PhD, Karen relocated to Denmark where she held postdoctoral positions in mycology and later in human cell cycle regulation, before moving to the world of drug discovery. Karen has been a full-time science writer since 2017, and has since then held numerous contract roles in science communication and editing spanning diverse topics including diagnostics, molecular biology, and gene therapy. Her broad research background provides the technical know-how to support scientists in diverse areas, and this in combination with her passion for learning helps her to keep abreast of exciting research developments as they unfold. Karen is currently based in Ireland, and you can follow her on Linkedin here.