Neutrophil
Body’s first line of defense against pathogens
Credit: Art by Nelly Aghekyan. Set in motion by Dr. Emanuele Petretto. Words by Dr. Eshita Paul. Coordinator: Dr. Masia Maksymowicz, Series Director: Dr. Radhika Patnala
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Philipp Dettmer called them the crazy, suicidal Spartan warriors of the immune system (Immune). Yes, we are talking about neutrophils, which are crucial to the host’s defense against all infectious pathogens. As the vanguard of the innate arm of immunity, neutrophils internalize, destroy, and digest the pathogen cells — a process that is thought to be non-specific and straightforward (1). They are also important modulators of inflammation (2).
That friend who is always ready to help!
Neutrophils, also known as polymorphonuclear leukocytes (PMNs), are the primary type of white blood cells in humans. They stand out with their distinct segmented nuclei and granules. Their nucleus, with a “pearls-on-a-string” configuration of five or more lobes, facilitates quicker migration and provides great flexibility, especially across confined places, making them the first responders to infection. They migrate to the site of inflammation, ready to eliminate potential invaders (3). Originating from the hematopoietic stem cells in bone marrow, they enter the circulation and travel to the tissues, where they carry out their mission before being swiftly removed by macrophages.
The bone marrow produces ~ a staggering 1011 neutrophils daily, making them the most prevalent type of white blood cell. The bone marrow also comprises a reserve of mature neutrophils, approximately 20 times the number of neutrophils in circulation, a pool ready for on-demand release (4).
The way we spend our time defines who we are…
Initially, it was believed that neutrophils only survive for a few hours outside of the bone marrow before being phagocytosed and eliminated. This few-hour existence was well suited to the notion of their predefined trajectory. However, further research, including in vivo labeling experiments, has suggested they may live for a few days. This extended lifespan also challenges the paradigm that neutrophils are short-lived cells generated in large quantities just to destroy microorganisms (5).
It has become evident that neutrophils serve purposes other than eliminating infections, which was inconsistent with their claimed half-life of 5 hours. Because of their much-extended lifespan, new roles for neutrophils (e.g., in shaping inflammatory diseases) can now be predicted.
The graceful exit from the bone marrow
Mature neutrophils can exit the bone marrow and enter the bloodstream via a carefully regulated release. In a healthy organism, only 1–2% of total neutrophils are present in the blood, and the rest are in the bone marrow. CXCR2 and CXCR4, two chemokine receptors, work together to maintain mature neutrophils in the bone marrow (6). In order to preserve the neutrophils in the bone marrow, osteoblasts and other bone marrow stromal cells help by expressing CXCL12 to keep the CXCR4-CXCL12 connection. On the other hand, G-CSF breaks this connection, which causes neutrophils to leave the bone marrow (7). Furthermore, endothelial cells outside the bone marrow produce ligands for CXCR2, such as CXCL1, CXCL2, CXCL5, and CXCL8, when neutrophil mobilization into the bloodstream is required (8). G-CSF is the main protagonist that stimulates the discharge of neutrophils, by causing megakaryocytes to upregulate CXCR2 ligands, bone marrow stroma cells to express CXCL12 less frequently, and neutrophils themselves to express CXCR4 less frequently (9). A network of cytokines, including interleukin (IL)-23 from phagocytes and IL-17 from T lymphocytes, also controls neutrophil production outside the bone marrow (10,11).
Rock and roll is not just music; it is a way of life
The action of the leukocyte adhesion cascade mobilizes blood-derived neutrophils to areas of infection or inflammation. Neutrophils roll on the endothelium when endothelial cells that are close to the afflicted spot become activated and start expressing adhesion receptors. Chemokines then activate the neutrophil, causing strong adherence and migration into surrounding tissues. The process of neutrophil activation involves two steps: priming, which involves first exposure to mediators like cytokines, followed by degranulation and oxidative metabolism of the cells (12). Once activated, neutrophils transmigrate to the tissues and follow the chemoattractant gradients to accomplish their tasks (13). Along with phagocytosis, neutrophils release neutrophil extracellular traps (NETs), which increase the natural defences against invasive microorganisms’ effectiveness when phagocytosis is thwarted or ineffectual. NETs provide a three-dimensional framework that draws in and holds onto participants in the humoral innate immune response.
Signals from the sympathetic nervous system also regulate the number of neutrophils in the blood. Adrenergic neurons cause endothelial cells to produce adhesion molecules in a time-sensitive manner, which permits neutrophils to exit the bloodstream. This control follows the circadian rhythm (14).
Once within tissues, neutrophils undergo apoptosis before being phagocytosed by local dendritic and macrophage cells. Senescent neutrophils in the circulation activate CXCR4 expression, enabling them to return to the bone marrow for ultimate clearance. For the bone marrow to regulate the generation of neutrophils, apoptotic neutrophils must be first removed (15).
Roles that go beyond protecting the host
In vitro research on neutrophils has significantly altered our understanding of their function in the immune system. Direct or indirect interactions between neutrophils and immune cells involved in innate and adaptive have been shown to facilitate the active control of diverse immune cells. Interactions between natural killer (NK) cells, lymphocytes, mesenchymal stem cells, DCs, monocytes, and macrophages in vitro have all been demonstrated with neutrophils. Additionally, regulatory T cells and platelets are also included in the crosstalk. Growth of NK cells in both the bone marrow and the peripheral areas depends on neutrophils. By producing ROS and releasing granules, they can influence the NK cells’ ability to survive, proliferate, exhibit cytotoxic activity, and produce interferon γ (IFNγ). By releasing various chemokines, neutrophils and lymphocytes can regulate each other’s recruitment to the infection site. Apoptotic neutrophils interact with monocytes to cause them to produce less pro-inflammatory cytokines, such as TNF-α and IL-1β, and to trigger an anti-inflammatory cytokine reaction via IL-10 and TGF-β (16).
Neutrophils have been shown to express genes producing inflammatory mediators. They were also found to create anti-inflammatory chemicals and factors that promote the resolution of inflammation. These novel findings significantly impact our comprehension of inflammatory illnesses, how they might be treated, and whether or not neutrophils can be used as immune modulation targets.
Neutrophils as potential new targets for treatment
A growing body of research links neutrophils to the etiology of several human illnesses, including Neutrophil-specific granule deficiency (SGD), Neutrtropenia, Leucocyte adhesion deficiency (LAD), Chediak Higashi syndrome, several cancers, and neurodegenerative diseases, etc. The role of neutrophils varies depending on the type of disease and is influenced by factors such as age, circadian variations, disease progression, and changes in the microbiome. In situations when neutrophil function is inadequate, such as in case of severe bacterial or fungal infections, it is necessary to increase the overall activity of the neutrophil compartment. On the other hand, attenuation of the neutrophil compartment is sought in some disorders (like rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), etc.) that are characterized by excessive neutrophil activity. Other situations (such as sepsis or cancer) cause neutrophils’ regular function to change into a harmful, aberrant phenotype or “derailment.”
In order to treat some of these diseases, several ongoing investigations are exploring ways to manipulate neutrophils. Some therapeutic approaches being investigated include neutrophil production and development, disrupting the buildup of neutrophils at the location of infection or inflammation, and undoing the harmful changes in neutrophil phenotype that occur during specific pathological conditions. Mitigating the adverse effects of neutrophil extracellular traps (NETs) is another important tactic. Numerous neutrophil-targeted treatment approaches are starting to make their way into clinical practice. For example, CXCR2 antagonists and neutrophil elastase inhibitors have been explored in clinical trials for several human diseases.
It is anticipated that in the years to come, biological and small-molecule therapies that target the neutrophil population to encourage stimulation, suppression, or maybe even elimination of these cells will become more prevalent. Additionally, recent research suggests that neutrophils may be used as vehicles for therapeutic nanoparticles (17). Certain criteria may apply to utilizing neutrophil-derived compounds as therapeutic agents, such as granule proteins and peptides, to create new antibacterial instruments. When combined, these opportunities portend an exciting new age in the study of human illnesses that target neutrophils (18–21).
Recognizing and appreciating the labs working in this space
- Dr. Jonathan Reichner, Department of Surgery, Brown University, USA. (https://surgery.med.brown.edu/divisions/surgical-research/laboratories/reichner-lab, LinkedIn profile
- Dr. Tanya Mayadas, Department of Pathology, Harvard Medical School, USA. (https://mayadaslab.bwh.harvard.edu/), LinkedIn profile
- Dr. Hongbo R. Luo, Harvard Medical School, USA.(https://www.childrenshospital.org/research/labs/luo-laboratory-research)
- Dr. Sussan Nourshargh, Queen Mary University of London, UK.(https://www.centre-for-microvascular-research.com/noursharg-lab), @NoursharghLab
- Dr Borko Amulic, University of Bristol, UK.(https://www.bristol.ac.uk/people/person/Borko-Amulic-7f48170b-3c68-470c-a56c-cf1aa0978cba/), @Bristolneutlab
- Dr. Arturo Zychlinsky, Max Planck Institute for Infection Biology, Berlin, Germany. (https://www.mpiib-berlin.mpg.de/2150386/arturo-zychlinsky1), @zychlinsky
- Dr. Lai Guan Ng, Singapore Immunology Network (SIgN), A*STAR, Singapore. (https://research.a-star.edu.sg/researcher/lai-guan-ng/), @lai9uan, LinkedIn profile
- Dr. Mikala Egeblad, Cold Spring Harbor Laboratory, USA. (https://egebladlab.labsites.cshl.edu/), @megeblad, Egeblad Laboratory
- Dr. Mia Phillipson, Uppsala University, Sweden. (https://www.uu.se/en/department/medical-cell-biology/research/research-groups/mia-phillipson), @PhillipsonMia
- Dr. Bruce D. Levy, Brigham and Women’s Hospital, USA. (https://levylab.bwh.harvard.edu/), @BDLevyLab
References
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2. Cassatella MA. Neutrophil-derived proteins: selling cytokines by the pound. Adv Immunol. 1999;73:369–509.
3. Bekkering S, Torensma R. Another look at the life of a neutrophil. World Journal of Hematology. 2013 May 6;2(2):44–58.
4. Dancey JT, Deubelbeiss KA, Harker LA, Finch CA. Neutrophil kinetics in man. J Clin Invest. 1976 Sep;58(3):705–15.
5. Pillay J, den Braber I, Vrisekoop N, Kwast LM, de Boer RJ, Borghans JAM, et al. In vivo labeling with 2H2O reveals a human neutrophil lifespan of 5.4 days. Blood. 2010 Jul 29;116(4):625–7.
6. Eash KJ, Greenbaum AM, Gopalan PK, Link DC. CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow. J Clin Invest. 2010 Jul;120(7):2423–31.
7. Metcalf D. Hematopoietic cytokines. Blood. 2008 Jan 15;111(2):485–91.
8. ter Huurne M, Figdor CG, Torensma R. Hematopoietic stem cells are coordinated by the molecular cues of the endosteal niche. Stem Cells Dev. 2010 Aug;19(8):1131–41.
9. Semerad CL, Liu F, Gregory AD, Stumpf K, Link DC. G-CSF is an essential regulator of neutrophil trafficking from the bone marrow to the blood. Immunity. 2002 Oct;17(4):413–23.
10. Gordy C, Pua H, Sempowski GD, He YW. Regulation of steady-state neutrophil homeostasis by macrophages. Blood. 2011 Jan 13;117(2):618–29.
11. Jiao J, Dragomir AC, Kocabayoglu P, Rahman AH, Chow A, Hashimoto D, et al. Central Role of Conventional Dendritic Cells in Regulation of Bone Marrow Release and Survival of Neutrophils. The Journal of Immunology. 2014 Apr 1;192(7):3374–82.
12. La G, Lc M, Pm H, Rb J. Priming of neutrophils for enhanced release of oxygen metabolites by bacterial lipopolysaccharide. Evidence for increased activity of the superoxide-producing enzyme. The Journal of experimental medicine [Internet]. 1984 Dec 1 [cited 2024 May 14];160(6). Available from: https://pubmed.ncbi.nlm.nih.gov/6096475/
13. Rosales C. Neutrophil: A Cell with Many Roles in Inflammation or Several Cell Types? Front Physiol [Internet]. 2018 Feb 20 [cited 2024 May 14];9. Available from: https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2018.00113/full
14. Scheiermann C, Kunisaki Y, Lucas D, Chow A, Jang JE, Zhang D, et al. Adrenergic nerves govern circadian leukocyte recruitment to tissues. Immunity. 2012 Aug 24;37(2):290–301.
15. Stark MA, Huo Y, Burcin TL, Morris MA, Olson TS, Ley K. Phagocytosis of Apoptotic Neutrophils Regulates Granulopoiesis via IL-23 and IL-17. Immunity. 2005 Mar 1;22(3):285–94.
16. Wang J, Wang J. Neutrophils, functions beyond host defense. Cellular Immunology. 2022 Sep 1;379:104579.
17. Chu D, Gao J, Wang Z. Neutrophil-Mediated Delivery of Therapeutic Nanoparticles across Blood Vessel Barrier for Treatment of Inflammation and Infection. ACS Nano. 2015 Dec 22;9(12):11800–11.
18. Malech HL, DeLeo FR, Quinn MT. The Role of Neutrophils in the Immune System: An Overview. In: Quinn MT, DeLeo FR, editors. Neutrophil: Methods and Protocols [Internet]. New York, NY: Springer US; 2020 [cited 2024 May 15]. p. 3–10. Available from: https://doi.org/10.1007/978-1-0716-0154-9_1
19. Németh T, Sperandio M, Mócsai A. Neutrophils as emerging therapeutic targets. Nat Rev Drug Discov. 2020 Apr;19(4):253–75.
20. Mócsai A. Diverse novel functions of neutrophils in immunity, inflammation, and beyond. J Exp Med. 2013 Jul 1;210(7):1283–99.
21. Coffelt SB, Wellenstein MD, de Visser KE. Neutrophils in cancer: neutral no more. Nat Rev Cancer. 2016 Jul;16(7):431–46.
About the author:
Dr. Eshita Paul
Content Editor The League of Extraordinary Cell Types, Sci-Illustrate Stories
Dr. Paul did her Ph.D. in Biochemical Engineering (Constructor University, Germany), studying the outer membrane channels and efflux pumps of Gram-negative bacteria in the context of antibiotic resistance. Currently, she is working on pediatric rare genetic disorders at the Centre for DNA Fingerprinting and Diagnostics in India. Dr. Paul is passionate about scientific storytelling and an ardent admirer of scientific illustrations. In her free time, she enjoys listening to podcasts and decorating the home.
About the artist:
NELLY AGHEKYAN
Contributing Artist The League of Extraordinary Cell Types, Sci-Illustrate Stories
Nelli Aghekyan, did a bachelor’s and master’s in Architecture in Armenia, after studying architecture and interior design for 6 years, she concentrated on her drawing skills and continued her path in the illustration world. She works mainly on children’s book illustrations, some of her books are now being published. Currently living in Italy, she works as a full-time freelance artist, collaborating with different companies and clients.
About the animator:
DR. EMANUELE PETRETTO
Animator The League of Extraordinary Cell Types, Sci-Illustrate Stories
Dr. Petretto received his Ph.D. in Biochemistry at the University of Fribourg, Switzerland, focusing on the behavior of matter at nanoscopic scales and the stability of colloidal systems. Using molecular dynamics simulations, he explored the delicate interaction among particles, interfaces, and solvents.
Currently, he is fully pursuing another delicate interaction: the intricate interplay between art and science. Through data visualization, motion design, and games, he wants to show the wonders of the complexity surrounding us.
About the series:
The League of Extraordinary Cell types
The team at Sci-Illustrate and Endosymbiont bring to you an exciting series where we dive deep into the wondrous cell types in our body, that make our hearts tick ❤.
