In our last article, we introduced mast cells, their origins and morphology, and summarized how they are activated during IgE-mediated allergic responses. Here, we shift gears and explore how mast cells, together with microglia and the blood brain barrier, contribute to inflammation in the central nervous system. After a quick recap on microglia and the blood brain barrier, we will summarize what is currently understood about their roles in central nervous system inflammation and touch upon what can happen when neuroinflammation becomes chronic.
So, what is neuroinflammation?
Inflammation is an ancient yet highly complex immune response to protect tissue, remove harmful material and promote healing of any damage that has occurred. When this happens within the central nervous system (CNS), it is known as neuroinflammation. Inflammation outside of the CNS is known as peripheral inflammation. Neuroinflammation is distinct from peripheral inflammation, which involves a cascade of events mediated by neutrophils, monocytes (macrophages and dendritic cells), leukocytes and mast cells.
Neuroinflammation is initiated in response to altered CNS homeostasis, during which microglia and astrocytes are activated, inflammatory mediators and secondary messengers are released, and reactive oxygen- and reactive nitrogen species are produced. These events culminate in immune, physiological, and biochemical consequences to neutralize the threat and promote healing of injury or other damage.
When uncontrolled, neuroinflammation may contribute to neurodegeneration and disease. Research carried out in the last 20 years has revealed extensive communication between the immune system and the CNS, and although not well understood, the interaction between mast cells and microglia is believed to be critical to this process.
Before we go into more detail about what happens during neuroinflammation, let’s take a recap on the major cell types involved.
A recap on microglia and astrocytes
Microglia are the resident phagocytes of the CNS, where they comprise about one sixth of the brain’s total cell density and constitute the brain’s main line of defense. They express a unique repertoire of receptors including toll-like receptors, cytokine receptors, integrins, P2Y receptors and others, which allows them to detect threats and minute changes in brain homeostasis, and interact with neighboring cells including neurons, astrocytes, mast cells, and other immune cells.
Activated microglia accumulate at the site of infection or damage and produce an arsenal of proinflammatory cytokines, chemokines and reactive oxygen species (ROS); these are intended to kill the pathogen (ROS) and trigger an adaptive immune response by attracting leukocytes to the affected area. The release of inflammatory molecules may also activate nearby astrocytes to release additional proinflammatory signaling molecules to further amplify the response.
Astrocytes play a crucial role in regulating innate and adaptive immune responses to CNS injury, and depending on the stimuli received they may exert pro-inflammatory or immunosuppressive effects. You can read more about astrocytes in a previous article here, and their role in regulating neuroinflammation is extensively covered elsewhere (1, and references therein).
And what about mast cells again?
In case you missed our last article, mast cells are tissue-resident granulocytes that when activated, for example during an allergic reaction, release the contents of their granules to the cell exterior, triggering a powerful inflammatory reaction. Besides allergy and anaphylaxis, mast cells also play roles in inflammation, immune tolerance, tissue repair and angiogenesis, defense against toxins and parasites, and others.
Mast cells are found throughout the body including the CNS. Outside of the CNS, 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. In the CNS, mast cells are found in close proximity to the meninges of the spinal cord and the brain, which enables their participation in neuroinflammation.
It has been shown that mast cell-derived mediators, such as histamine and tryptase, can trigger microglial activation in rodent models of CNS inflammation (2, and references therein), and that unresolved microglial activation is a major cause of chronic neuroinflammation and irreversible CNS damage that may lead to neurodegeneration. The role of mast cells in chronic neuroinflammation has also received attention in recent years. For example, it has been shown that inflammatory, vasoactive and neurotoxic mediators released from mast cell granules can disrupt the blood brain barrier, alter blood flow to the brain and activate microglia (see 6 for a recent review on this topic).
The blood brain barrier
The blood brain barrier (BBB) is a highly regulated selective barrier found at the blood-to-brain interface. Its job is to protect neurons and glial cells and maintain brain homeostasis by preventing most pathogens, drugs, and other potentially harmful agents from non-selectively crossing into the extracellular fluid of the brain.
Some pathogens, e.g., the yeast Cryptococcus neoformans and the bacteria Streptococcus pneumonia (both of which cause meningitis), can traverse the BBB, and when this happens, microglia act as rapid responders to decrease inflammation and destroy the pathogens before neural damage occurs. Microglia also produce a number of growth and repair factors to activate other immune cells as mentioned above and promote repair of damaged CNS tissue after infection or other trauma.
Despite more than 100 years of research in this area, our picture of the human BBB and its mechanisms remains incomplete, but we have summarized what we do know in our BBB article series.
How does neuroinflammation occur – what we know in brief:
Neuroinflammation is a highly complex process that typically occurs in response to infection, disease, and injury. Its initiation and amplification is dependent on interactions between glial cells, immune cells and neurons, and the process of neuroinflammation is hallmarked by:
- Elevated levels of pro-inflammatory cytokines
- Microglial and mast cell activation
- Peripheral leukocyte infiltration and adaptive immune response
Neuroinflammation is typically initiated when inflammatory receptors on the surfaces of microglia detect that something is wrong. Stimulation of those receptors by damage- or pathogen-associated molecular patterns (DAMPs or PAMPs), via protein aggregates, virus or other pathogens, leads to activation of signal transducers which in turn activates transcription activators such as NF-κB and IRF3. This leads to the secretion of inflammatory mediators which further amplify inflammation. For example, the mediators produced by activated microglia directly trigger the infiltration of leukocytes to the affected site, initiating the beginning of an adaptive immune response.
Healthy neuroinflammation vs. neurodegeneration
A ‘normal’ level of neuroinflammation is crucial to protect and maintain CNS health. However, persistence of the inflammatory response beyond what is physiologically necessary can be detrimental and cause changes in the brain tissue structure, damage to the BBB, hyperexcitable neurons (that react very strongly to stimuli) and nerve cell death.
While chronic neuroinflammation is now acknowledged to contribute to or even cause CNS injury and increase the risk of neurodegenerative disease, researchers are just beginning to unravel how neuroinflammation can go from being healthy to a disease process.
So, what do we know so far? In brief, the efforts of activated microglia are intended to initiate a healthy inflammatory response that will kill pathogens and remove threats, and this response should cease when that threat is resolved. However, for reasons that are not fully understood, activated microglia and mast cells sometimes cause chronic inflammation which leads to neurotoxicity, BBB breakdown and the protein aggregation seen in classical neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Protein aggregates and DAMPs released from damaged nerve cells further amplify neuroinflammation and aggravate disease. Some protein aggregates, for example, TDP-43 and α-synuclein, can directly induce neuronal death.
What about the immune-privileged status of the CNS?
Although the CNS was once considered immune-privileged thanks to the BBB, this status has been challenged in recent years, most notably following reports of neurotoxicity after CAR-T cell therapy, which is estimated to occur in more than 60% of treated patients with leukemia or lymphoma. This complication, known as immune effector cell-associated neurotoxicity syndrome or ICANS, can be fatal (3), and while the mechanisms are not yet understood, BBB dysfunction is frequently seen in affected patients. A recent review of 100 scientific articles covering CAR-T related deaths found that most deaths are associated with BBB breakdown, central nervous system cell damage, and infiltrated T cells (4, and references therein).
The immune-privileged status of the CNS has also been called into question by the neurological symptoms seen during COVID-19 disease, especially in those suffering from long-term memory- and concentration difficulties (commonly referred to as long-COVID). These and other neurological symptoms such as loss of smell and taste have led researchers to speculate about whether SARS-CoV-2 can enter the brain. It has been shown that wild-type and omicron variants of SARS-CoV-2 can disrupt the BBB in vitro (5), but hard evidence for viral entry into the human brain is lacking. Rather than the virus entering the CNS, the consensus is that the acute and long-term neurological symptoms are caused by neuroinflammation, which is supported by raised levels of brain injury markers and inflammatory mediators during the acute phase of COVID-19 disease (7).
More research, more answers (and questions!), and hopes to treat neurodegenerative disease
While researchers slowly unravel what happens during neuroinflammation and neurodegeneration, most studies raise more questions than they answer.
For instance, the pathobiology of Alzheimer’s disease has been studied since the early 1900s and many potential causes have been hypothesized, but more than 100 years later, clinical trials to bring new therapies are failing because we still do not know what causes the disease. Getting the answers to those questions will reveal therapeutic targets and help pave the way for new therapies.
Interested in learning more about the human BBB? Stay tuned for more from our BBB series.
References
- Colombo E, Farina C. Astrocytes: Key Regulators of Neuroinflammation. Trends Immunol. 2016 Sep;37(9):608-620.
- Sandhu JK, Kulka M. Decoding Mast Cell-Microglia Communication in Neurodegenerative Diseases. Int J Mol Sci. 2021 Jan 22;22(3):1093. doi: 10.3390/ijms22031093.
- Gilbert, M. J. (2017). Severe neurotoxicity in the phase 2 trial of JCAR015 in adult B-ALL (ROCKET study): analysis of patient, protocol and product attributes. Proceedings from the Society for Immunotherapy of Cancer, 8-12.
- Del Duca F, Napoletano G, Volonnino G, Maiese A, La Russa R, Di Paolo M, De Matteis S, Frati P, Bonafè M, Fineschi V. Blood-brain barrier breakdown, central nervous system cell damage, and infiltrated T cells as major adverse effects in CAR-T-related deaths: a literature review. Front Med (Lausanne). 2024
- Taquet M, Skorniewska Z, Hampshire A, et al; PHOSP-COVID Study Collaborative Group. Acute blood biomarker profiles predict cognitive deficits 6 and 12 months after COVID-19 hospitalization. Nat Med. 2023 Oct;29(10):2498-2508.
- Hendriksen E, van Bergeijk D, Oosting RS, Redegeld FA. Mast cells in neuroinflammation and brain disorders. Neurosci Biobehav Rev. 2017 Aug;79:119-133. doi: 10.1016/j.neubiorev.2017.05.001.
- Michael BD, Dunai C, Needham EJ, et al; ISARIC4C Investigators; COVID-CNS Consortium; Taams LS, Menon DK. Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses. Nat Commun. 2023 Dec 22;14(1):8487.
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.
