The brain’s immune system
The brain is the center of the organism that gathers information and sends orders to other parts of the body. As such, it must be protected from pathogens and other dangers that are trying to invade humans every day. For many years researchers believed that the brain is isolated from the rest of the body, including the immune system. Paul Ehrlich, a German physician, tested it by injecting a mouse with a dye, that quickly spread to every tissue except the brain and spinal cord. Thus, the blood-brain barrier was discovered (1). Now we know that the brain is interconnected to the rest of the body, and, this communication, and the relay of cells inside and out of the brain, are well controlled by microvascular epithelial cells, astrocytes, and pericytes (2).
The brain is an immune-privileged tissue, having its own set of special immune cells that have evolved to specifically cater to the various demanding needs of the brain, its development, function, maintenance, and in disease.
The major cell types that protect the brain are: microglia, central nervous system–associated macrophages, and astrocytes (which we discussed previously) (3). Microglia (or microglial cells) are found everywhere in the central nervous system (CNS), although their number differs between the parts of the brain (4). They are the only immune cells found in the CNS parenchyma (the functional part of the brain that contains neurons and glial cells) (3). During early embryonic development, they migrate to CNS, where they then proliferate while remaining able to self-renew throughout life. In CNS, they are responsible for the development, homeostasis, and activation of immunity, protecting the brain from damage and infections (5). They are also called brain macrophages, as they play a similar role by clearing away dead cells, pathogens, and debris.
Multiple functions of microglia
Although best known for their role in brain immunity, microglial cells have many important functions. Interestingly, these functions are comparable among species, since the basic transcriptional microglial profile was shown to be conserved (3, 6).
During embryogenesis, microglial cells take part in vasculogenesis (development of blood vessels) in the retina (7). They also are responsible for helping in the migration of neurons as well as removing unnecessary ones, which were needed during development and are now excess. It was shown that even when other glial cells are missing, microglia play a critical role in the development of neuronal network (3).
In an adult organism, microglia regulate neuronal pruning, activation, and survival, but also the homeostasis of myelination (3). They have an amazing quality to rapidly change their shape. Microglia change their morphology according to their status: from resting (or ramified) to active (or amoeboid) (8). Currently, scientists agree that microglia can transform both their shape and functions as a response to neuronal insult (8). They become more ameboid, which helps them migrate to the place of injury. This also results in increased phagocytosis as well as secretion of cytokines and chemokines, which stimulates other brain cells to fight the illness (3, 8, 9).
Microglia sex-dependent heterogeneity
To better understand the functions of microglial cells, scientists introduced a novel method called single-cell RNASeq, which allows analysis of the gene transcription of every single cell present in the analyzed tissue. This way they discovered that actually, microglia are a very heterogenous cell type (6). This is especially interesting when we compare the response of microglia to cancer (e.g. glioma) between males and females (10–12). Male mouse’s microglia were more frequent in specific brain areas and were more responsive (10). They also had higher expression of major histocompatibility complex II (MHCII) genes, which researchers suggested to result in stronger activation of these microglia (12). Thus, it is very important to always take into account the sex, but also race, when studying the response to treatment. It is now known that not only microglia, but also other cell types (including cancer cells) can be affected by the presence of sex hormones and the extracellular microenvironment.
Recognizing and appreciating the labs working in this space
- Professor S Thameem Dheen Laboratory, National University of Singapore, Singapore: https://medicine.nus.edu.sg/ant/Directory/Acad/Profiles/antstd.html
- Kaczmarek-Kaminska Lab, Nencki Institute of Experimental Biology, Poland: https://kaminska-lab.nencki.edu.pl/
- Stevens Lab, Harvard University, USA: https://www.stevenslab.org/ , Twitter: @stevens1lab
- Florent Ginhoux Lab, Gustave Roussy, France: https://www.gustaveroussy.fr/en/florent-ginhoux
- Deczkowska Lab, Institut Pasteur, France: https://www.aleksdelab.com/ , Twitter: @AleksDeLab
- Siegert Lab, ISTA, Austria: https://ist.ac.at/en/research/siegert-group/
- Michelucci Lab, Luxembourg Institute of Health, Luxembourg: https://www.lih.lu/en/research-scope/research-department/department-of-cancer-research/neuro-immunology-group/
- Erny Group, Institute of Neuropathology, Freiburg, Germany: https://www.uniklinik-freiburg.de/neuropathology/research/cns-myeloid-cell-immunology-dr-d-erny.html
- Amit Lab, Weizmann Institute of Science, Israel: https://www.weizmann.ac.il/immunology/AmitLab/ , Twitter: @IdoAmitLab
- S. Wolf Lab, Max-Delbrück-Centrum für Molekulare Medizin, Germany: https://www.mdc-berlin.de/s-wolf
- Quintana Lab, Brigham and Women’s Hospital, Boston, USA: https://quintanalab.bwh.harvard.edu/research/ , Twitter: @QuintanaLabHMS
References:
- Götz, Jürgen and Woodruff, Alan “Explainer: what is the blood-brain barrier and how can we overcome it?” (2017) https://theconversation.com/explainer-what-is-the-blood-brain-barrier-and-how-can-we-overcome-it-75454
- Mohammad, Nabila Sher et al. “Effects of lipid based Multiple Micronutrients Supplement on the birth outcome of underweight pre-eclamptic women: A randomized clinical trial.” Pakistan journal of medical sciences vol. 38,1 (2022): 219–226. doi:10.12669/pjms.38.1.4396
- Prinz, Marco et al. “Microglia and Central Nervous System-Associated Macrophages-From Origin to Disease Modulation.” Annual review of immunology vol. 39 (2021): 251–277. doi:10.1146/annurev-immunol-093019–110159
- Soulet, Denis, and Serge Rivest. “Microglia.” Current biology : CB vol. 18,12 (2008): R506–8. doi:10.1016/j.cub.2008.04.047
- Vidal-Itriago, Andrés et al. “Microglia morphophysiological diversity and its implications for the CNS.” Frontiers in immunology vol. 13 997786. 19 Oct. 2022, doi:10.3389/fimmu.2022.997786
- Geirsdottir, Laufey et al. “Cross-Species Single-Cell Analysis Reveals Divergence of the Primate Microglia Program.” Cell vol. 179,7 (2019): 1609–1622.e16. doi:10.1016/j.cell.2019.11.010
- Checchin, Daniella et al. “Potential role of microglia in retinal blood vessel formation.” Investigative ophthalmology & visual science vol. 47,8 (2006): 3595–602. doi:10.1167/iovs.05–1522
- Vidal-Itriago, Andrés et al. “Microglia morphophysiological diversity and its implications for the CNS.” Frontiers in immunology vol. 13 997786. 19 Oct. 2022, doi:10.3389/fimmu.2022.997786
- Dheen, S Thameem et al. “Microglial activation and its implications in the brain diseases.” Current medicinal chemistry vol. 14,11 (2007): 1189–97. doi:10.2174/092986707780597961
- Guneykaya, Dilansu et al. “Transcriptional and Translational Differences of Microglia from Male and Female Brains.” Cell reports vol. 24,10 (2018): 2773–2783.e6. doi:10.1016/j.celrep.2018.08.001
- Maes, Margaret E et al. “Mitochondrial network adaptations of microglia reveal sex-specific stress response after injury and UCP2 knockout.” iScience vol. 26,10 107780. 29 Aug. 2023, doi:10.1016/j.isci.2023.107780
- Ochocka, Natalia et al. “Single-cell RNA sequencing reveals functional heterogeneity of glioma-associated brain macrophages.” Nature communications vol. 12,1 1151. 19 Feb. 2021, doi:10.1038/s41467–021–21407-w
About the author:
DR. MAŁGORZATA ‘MASIA’ MAKSYMOWICZ
Content Editor The League of Extraordinary Cell Types, Sci-Illustrate Stories
Dr. Maksymowicz did her Ph.D. in Cell Biology (IIMCB, Poland) studying the intracellular trafficking and inflammatory signalling of a cytokine receptor. She did a 1-year post-doc at Nencki Institute, Poland, studying the protein- and RNA-binding properties of proteins. Currently, she is doing a post-doc at Barts Cancer Institute, UK, studying the links between endocytosis and tumorigenesis. Dr. Maksymowicz is passionate about science and loves to combine different fields of biology, always trying to seek beauty in nature.
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 ❤.
