Mast Cells

Ever wonder what happens when you get stung by a bee or, worse, a scorpion? What about snakes? Are you immediately doomed, or is there still hope? Drum roll: mast cells to the rescue. Identified over 150 years ago, mast cells have emerged as powerful sentinels of the immune system that also fight off venom. Paul Ehrlich, who won a Nobel Prize in Medicine or Physiology for his work in the field of immunology, characterised these cells by staining them with aniline dyes in 1879 as part of his doctoral thesis work [1, 2].

Mast cells arise from myeloid precursor cells in the bone marrow. They are found all over the body: as immature cells in circulation and mature cells once in tissue. They are predominantly positioned in tissues interacting with the external environment, such as skin, lungs and gastrointestinal tract, which allows them to act as sentinel cells that mount a strong defence response against pathogens [3]. When a harmful substance is detected, immature mast cells from the blood rush to the affected tissue where they mature and join the fight [4].

Mast cells are rich is granules

Named ‘mastzellen’ by Paul Ehrlich for the German word ‘mast’ (meaning ‘fattening’), these cells contain so many granules that the nucleus is obscured. Although incorrectly hypothesised to provide nutrition to neighbouring cells, these granules arm mast cells with the necessary tools to perform various tasks which are key to the mast cells’ multifunctional prowess. These secretory granules are rich in functionally diverse mediators: heparin and histamine, which are involved in allergic and inflammatory responses; cytokines such as IL-3, which activate basophils and eosinophils; proteases such as chymase, which are involved in arthritis and allergic reactions in the airway; cytokines such as Tumour Necrosis Factor-alpha (TNF-α), which are involved in inflammation; and chemokines such as IL-8, which recruit granulocytes and monocytes (pro-inflammatory) to the sites of infection [2, 3]. Equipped with a variety of mediators, mast cells are multifunctional immune cells that orchestrate the defence response.

Mast cells defend against pathogens

Like other immune cells, mast cells can recognize pathogens by expressing various pattern recognition receptors, such as Toll-like receptors (TLRs), and receptors for bacteria-derived toxins, including E. coli hemolysin. This allows them to respond to pathogenic invasion by secreting cytokines, chemokines and other mediators that contribute to the fight against infection through diverse mechanisms. Additionally, these cells can indirectly detect pathogens by utilising receptors, including Fc receptors, which bind to pathogen-associated antibodies, and complement receptors. These receptors are central components of the inflammatory response initiated by the immune system [4, 5]. Additionally, there is diversity in the expression of the receptors on mast cells based on location, developmental stage and exposure to inflammatory factors adding to the complexity of these cells [6].

Mast cells neutralise venom

Millions of people fall prey to snake bites every year, often with deadly consequences [7]. The venom contains toxins that can rapidly promote tissue damage, and it has been suggested that mast cells are recruited by venom. However, mast cells were also believed to promote tissue damage and shock in response to snake venom. Recent studies have shown that this is far from the truth. In fact, mast cells possess receptors for an endogenous peptide, endothelin-1 peptide (ET-1), which is structurally similar to sarafotoxin — a component commonly found in snake venom. The structural similarity of sarafotoxin to ET-1, which reduces toxicity after bacterial infection, led to the hypothesis that mast cells might play a protective role against venom [8]. A study by Metz et al. showed that mast cells reduced the harmful effect of snake venom by releasing the protease, carboxypeptidase. They also showed that mast cells detected sarafotoxin through ET-1 receptors as postulated. Additionally, they found that mast cells reduced the toxicity of bee venom [9]. However, as the study was performed in mice, it is possible that the proteases released in humans and other mammals might be different. Given that mast cells possess a large and diverse number of granules, it is likely that mast cells have been selected to protect against a wide variety of snake and insect venom.

Mast cells play a dual role in cancer

When mast cells are activated, the release of powerful mediators from their granules can lead to a cascade of events that can play a role in tumour growth. In some cases, they play a positive role in fighting cancers, such as ovarian cancer, whereas in other cases, such as breast cancer, their involvement leads to a negative outcome [10,11]. For example, the release of TNF-α can result in tumour cell death or growth depending on the local environment [12,13]. In turn, protease and growth factor (PDGF-β) release promote the growth of extracellular matrix and vasculature in the tumour [6]. Many other mediators play a role in tumour growth as well. However, these mediators also engage the immune system by recruiting immune cells such as CD8/CD4 T cells, natural killer cells, regulatory T cells, and dendritic cells to name a few. Unfortunately, the recruited immune cells can either suppress tumours or enable tumour growth [14]. The overall impact of mast cell activation and immune cell recruitment varies based on the location, which makes the role of mast cells in cancer very complex and difficult to ascertain. However, mast cells are being studied as viable targets for cancer therapies [6].

Mast cells have remained a mystery because of the challenges associated with experimental design. However, recent advances have made it easier to study them as well as examine the mechanisms through which they perform various functions. Scientists have only scratched the surface when it comes to understanding their structural and functional heterogeneity.

Recognizing and appreciating the labs working in this space

• Galli Lab, Departments of Pathology, Stanford University School of Medicine, California, USA. https://med.stanford.edu/gallilab/events/event-1.html
• Piliponsky Lab, Center for immunity and immunotherapies, Seattle Children’s Research Institute, Washington State, USA. https://piliponskylab.org/
• Peter Valent, Department of Medicine I, Medical University of Vienna, Vienna, Austria. https://innere-med-1.meduniwien.ac.at/en/our-departments/haematologie-und-haemostaseologie-en/staff-members/univ-prof-dr-med-univ-peter-valent/
• Mast Cell Biology — Research group Gunnar Nilsson, Karolinska Instutet, Sweden. https://ki.se/en/research/research-areas-centres-and-networks/research-groups/mast-cell-biology-research-group-gunnar-nilsson
• Dwyer Lab, Harvard University, USA. https://dwyerlab.bwh.harvard.edu/
• John Schroeder Lab, Johns Hopkins University, USA. https://www.hopkinsmedicine.org/research/labs/j/john-schroeder-lab twitter: @HopkinsMedicine
• UK Mastocytosis Support Group, https://ukmasto.org/uk-masto/#gsc.tab=0 twitter: @UkMastocytosis
• The Mathias Laboratory, University of Connecticut, USA. https://mathiaslab.nusc.uconn.edu/
• Pullen Lab, University of Northern Colorado, USA. https://www.unco.edu/nhs/biology/about-us/labs/pullen-nicholas/ twitter: @UNCOBio
• Abraham Laboratory, Duke University School of Medicine, USA. https://abrahamlab.wixsite.com/abrahamlab
• Respiratory Immunology Lab, Harvard Medical School, USA. https://barrettlab.bwh.harvard.edu/research/
• European Mast Cell and Basophil Research Network, https://embrn.eu/

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References

1. Beaven, M. A. “Our Perception of the Mast Cell from Paul Ehrlich to Now.” Eur J Immunol 39 1 (2009): 11–25.
2. Valent, P., et al. “Mast Cells as a Unique Hematopoietic Lineage and Cell System: From Paul Ehrlich’s Visions to Precision Medicine Concepts.” Theranostics 10 23 (2020): 10743–68.
3. da Silva, E.Z., M.C. Jamur, and C. Oliver, Mast cell function: a new vision of an old cell. J Histochem Cytochem, 2014. 62(10): p. 698–738.Trivedi, N. H., et al. “Mast Cells: Multitalented Facilitators of Protection against Bacterial Pathogens.” Expert Rev Clin Immunol 9 2 (2013): 129–38.
4. Piliponsky, A. M., and L. Romani. “The Contribution of Mast Cells to Bacterial and Fungal Infection Immunity.” Immunol Rev 282 1 (2018): 188–97.
5. Lichterman, J. N., and S. M. Reddy. “Mast Cells: A New Frontier for Cancer Immunotherapy.” Cells 10 6 (2021).
6. Pucca, M. B., et al. “History of Envenoming Therapy and Current Perspectives.” Front Immunol 10 (2019): 1598.
7. Rivera, J. “Snake Bites and Bee Stings: The Mast Cell Strikes Back.” Nat Med 12 9 (2006): 999–1000.
8. Metz, M., et al. “Mast Cells Can Enhance Resistance to Snake and Honeybee Venoms.” Science 313 5786 (2006): 526–30.
9. Chan, J. K., et al. “Mast Cell Density, Angiogenesis, Blood Clotting, and Prognosis in Women with Advanced Ovarian Cancer.” Gynecol Oncol 99 1 (2005): 20–5.
10. Reddy, S. M., et al. “Poor Response to Neoadjuvant Chemotherapy Correlates with Mast Cell Infiltration in Inflammatory Breast Cancer.” Cancer Immunol Res 7 6 (2019): 1025–35.
11. Déry, R. E., et al. “Redundancy or Cell-Type-Specific Regulation? Tumour Necrosis Factor in Alveolar Macrophages and Mast Cells.” Immunology 99 3 (2000): 427–34.
12. Wang, X., and Y. Lin. “Tumor Necrosis Factor and Cancer, Buddies or Foes?” Acta Pharmacol Sin 29 11 (2008): 1275–88.
13. Aponte-López, A., and S. Muñoz-Cruz. “Mast Cells in the Tumor Microenvironment.” Adv Exp Med Biol 1273 (2020): 159–73.

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Content Editor The League of Extraordinary Cell Types, Sci-Illustrate Stories

Dr. Nowrin Ahmed has a PhD in Behavioral and Neural Sciences from Rutgers University-Newark (NJ, USA) where she studied the interactions between the midline thalamus and the amygdala. Currently, she is a post-doctoral fellow at Rutgers University — Newark where she is studying amygdala circuits. Dr. Nowrin enjoys sharing the beauty of science with diverse audiences.

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