Posts tagged microglial cells
Articles and news from the latest research reports.
Malignant brain tumours can be transformed into benign forms
Cells of malignant brain tumours deceive our immune system so effectively that it starts working for them. But who lives by the sword, dies by the sword. Researchers from the Nencki Institute in Warsaw show how to deceive brain tumours and change malignant gliomas into benign forms.
The research team of Prof. Bożena Kamińska from the Nencki Institute of Experimental Biology of the Polish Academy of Sciences in Warsaw developed – so far only in animal model – a method of converting malignant gliomas (brain tumours) into benign forms. Since the cells of benign gliomas are subdued and sometimes even eliminated by the host’s immune system, the prospects for survival of sick animals significantly increase. This novel research was funded by the Polish National Science Centre.
The nervous system, including the brain, is inhabited, besides neurons and glial cells, by microglial cells. They support the nervous cells but also have important protective functions, patrolling the surroundings with their extenses and eliminating damaged or unnecessary cells. As macrophages of our immune system they also fight foreign bacteria, viruses and tumorous cells. Unfortunately, sometimes the glia cells themselves become cancerous. This is how brain tumours called gliomas form. However, they are not uniform entity and could differ significantly with respect to their behaviour and degree of malignancy. In benign variants the survival prospects for patients are quite high, while in the case of malignant gliomas few patients are expected to live longer than a year.
In 2007 the group of Prof. Kamińska showed that malignant gliomas can “re-program” the brain immune cells (microglia) to support tumour development instead of fighting it. Similarly the tumour even changed the protective immune cells recruited to the brain from blood and bone marrow (peripheral macrophages). The research to understand how the tumour deceives the host’s immune system and forces the microglial cells to support and foster its growth has taken several years.
The results of other research groups showed that in the case of breast cancer the factor responsible for changing the behaviour of tumour-infiltrating macrophages is the CSF1 protein, controlling the maturation of macrophages. Researchers from the Nencki Institute asked, whether a similar substance is not produces by the cells of the malignant gliomas.
Studies conducted by Prof. Kamińska’s group has shown that gliomas do not produce larger amounts of the CSF1 protein and this protein does not significantly impact tumour development. They were however lucky to discover the production of a different protein from the same family, the CSF2 protein. In benign tumours this protein was present in small amounts, while in malignant gliomas large amounts of it were discovered. Researchers from the Nencki Institute decided to investigate, whether this protein really influences tumour invasiveness. With the help of self-developed tools they turned off the gene responsible for the production of the CSF2 protein in glioma cells.
“We have observed that after turning off a single gene – the gene producing the CSF2 protein – the tumour cells stopped attracting the microglia and were not capable of converting these cells to support the tumour’s development. As a result the immune system started working as expected and the malignant tumour was transformed into a benign form. It did not disappear, but stopped growing”, says a PhD candidate Małgorzata Sielska from the Nencki Institute.
The protein responsible for “re-programming” the anti-tumour response and for high invasiveness of gliomas is present only in cancerous cells and is practically absent from healthy brain. Therefore researchers from the Nencki Institute suspect that when the gene responsible for its production is turned off in the brain, it would affect only the tumour.
Research on taming malignant brain tumours and converting them into benign forms has been conducted on mouse glioma cells growing in the brains of experimental animals, and published in the Journal of Pathology. Presently the group of Prof. Kamińska is checking the effectiveness of this method in the cells of human malignant gliomas. Preliminary results confirm that silencing one gene in human glioma cells growing in mouse brains also stops the growth of the tumour. Developing tools to turn off this gene’s expression, following the creation of appropriate carriers, will in the future open new possibilities for gene therapy in humans.
The findings has helped Nencki researchers develop small molecules (short peptides) which interfere with binding the CSF2 protein (expressed by tumorous cells) to the appropriate receptors on microglial cells. This way the signal coming from tumorous cells gets blocked and the microglia is prevented from “re-programming” itself. The developed molecules, together with relevant genetic tools, are covered by an international patent. Presently researchers work towards starting preclinical and clinical trials of this method.
The proposed solution holds great potential for therapies using small molecules – short peptides or in the case of gene therapy, short RNA silencing gene expression. Will this method really work? This will be confirmed by further experiments and tests. For Nencki researchers it is important that the patented molecules target only one fragment of the signalling pathway which functions between the cells of the malignant tumour and the microglia, thus guaranteeing that no other functions of the organism are affected. Moreover discovery of such an important signalling pathway encourages scientists to search for ways of blocking it in other places, which could be technically more feasible.
“Our research is investigative in nature and above all aims to explain why and how tumours develop. We conducted our research mostly on experimental models, mouse glioma cells or human glioma cells growing in mice. Therefore the road to develop drugs and therapies limiting the invasiveness of gliomas in human is still very long. Luckily we already discovered the molecule that is worth targeting”, sums up Prof. Kamińska.
LCSB discovers endogenous antibiotic in the brain
Scientists from the Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg have discovered that immune cells in the brain can produce a substance that prevents bacterial growth: namely itaconic acid.
Until now, biologists had assumed that only certain fungi produced itaconic acid. A team working with Dr. Karsten Hiller, head of the Metabolomics Group at LCSB and funded by the ATTRACT program of Luxembourg’s National Research Fund, and Dr. Alessandro Michelucci has now shown that even so-called microglial cells in mammals are also capable of producing this acid. “This is a ground breaking result,” says Prof. Dr. Rudi Balling, director of LCSB: “It is the first proof of an endogenous antibiotic in the brain.” The researchers have now published their results in the prestigious scientific journal PNAS.
Alessandro Michelucci is a cellular biologist, with focus on neurosciences. This is an ideal combination for LCSB with its focus on neurodegenerative diseases, and Parkinson’s disease especially – i.e. changes in the cells of the human nervous system. “Little is still known about the immune responses of the brain,” says Michelucci. “However, because we suspect there are connections between the immune system and Parkinson’s disease, we want to find out what happens in the brain when we trigger an immune response there.” For this purpose, Michelucci brought cell cultures of microglial cells, the immune cells in the brain, into contact with specific constituents of bacterial membranes. The microglial cells exhibited a response and produced a cocktail of metabolic products.
This cocktail was subsequently analysed by Karsten Hiller´s metabolomics group. Upon closer examination, the scientists discovered that production of one substance in particular - itaconic acid - was upregulated. “Itaconic acid plays a central role in the plastics production. Industrial bioreactors use fungi to mass-produce it,” says Hiller: ” The realisation that mammalian cells synthesise itaconic acid came as a major surprise.”
However, it was not known how mammalian cells can synthesise this compound. Through sequence comparisons of the fungi’s enzyme sequence to human protein sequences, Karsten Hiller then identified a human gene, which encodes a protein similar to the one in fungi: immunoresponsive gene 1, orIRG1for short – a most exciting discovery as the function of this gene was not known. Says Hiller: "When it comes toIRG1, there is a lot of uncharted territory. What we did know is that it seems to play some role in the big picture of the immune response, but what exactly that role was, we were not sure."
To change this situation, the team turned offIRG1in cell cultures and instead added the gene to cells that normally do not express it. The experiments confirmed that in mammals,IRG1codes for an itaconic acid-producing enzyme. But why? When immune cells like macrophages and microglial cells take up bacteria in order to inactivate them, the intruders are actually able to survive by using a special metabolic pathway called the glyoxylate shunt. According to Hiller, "macrophages produce itaconic acid in an effort to foil this bacterial survival strategy.The acid blocks the first enzyme in the glyoxylate pathway. Which is how macrophages partially inhibit growth in order to support the innate immune response and digest the bacteria they have taken up."
LCSB director Prof. Dr. Rudi Balling describes the possibilities that these insights offer: “Parkinson’s disease is highly complex and has many causes. We now intend to study the importance of infections of the nervous system in this respect – and whether itaconic acid can play a role in diagnosing and treating Parkinson’s disease.”
(Source: wwwen.uni.lu)
Suppressing Protein May Stem Alzheimer’s Disease Process
Scientists funded by the National Institutes of Health have discovered a potential strategy for developing treatments to stem the disease process in Alzheimer’s disease. It’s based on unclogging removal of toxic debris that accumulates in patients’ brains, by blocking activity of a little-known regulator protein called CD33.
“Too much CD33 activity appears to promote late-onset Alzheimer’s by preventing support cells from clearing out toxic plaques, key risk factors for the disease,” explained Rudolph Tanzi, Ph.D., of Massachusetts General Hospital and Harvard University, a grantee of the NIH’s National Institute of Mental Health (NIMH) and National Institute on Aging (NIA). “Future medications that impede CD33 activity in the brain might help prevent or treat the disorder.”
Tanzi and colleagues report on their findings April 25, 2013 in the journal Neuron.
“These results reveal a previously unknown, potentially powerful mechanism for protecting neurons from damaging toxicity and inflammation,” said NIMH Director Thomas R. Insel, M.D. “Given increasing evidence of overlap between brain disorders at the molecular level, understanding such workings in Alzheimer’s disease may also provide insights into other mental disorders.”
Variation in the CD33 gene turned up as one of four prime suspects in the largest genome-wide dragnet of Alzheimer’s-affected families, reported by Tanzi and colleagues in 2008. The gene was known to make a protein that regulates the immune system, but its function in the brain remained elusive. To discover how it might contribute to Alzheimer’s, the researchers brought to bear human genetics, biochemistry and human brain tissue, mouse and cell-based experiments.
They found over-expression of CD33 in support cells, called microglia, in postmortem brains from patients who had late-onset Alzheimer’s disease, the most common form of the illness. The more CD33 protein on the cell surface of microglia, the more beta-amyloid protein and plaques – damaging debris – had accumulated in their brains. Moreover, the researchers discovered that brains of people who inherited a version of the CD33 gene that protected them from Alzheimer’s conspicuously showed reduced amounts of CD33 on the surface of microglia and less beta-amyloid.
Brain levels of beta-amyloid and plaques were also markedly reduced in mice engineered to under-express or lack CD33. Microglia cells in these animals were more efficient at clearing out the debris, which the researchers traced to levels of CD33 on the cell surface.
Evidence also suggested that CD33 works in league with another Alzheimer’s risk gene in microglia to regulate inflammation in the brain.
The study results – and those of a recent rat study that replicated many features of the human illness – add support to the prevailing theory that accumulation of beta-amyloid plaques are hallmarks of Alzheimer’s pathology. They come at a time of ferment in the field, spurred by other recent contradictory evidence suggesting that these presumed culprits might instead play a protective role.
Since increased CD33 activity in microglia impaired beta-amyloid clearance in late onset Alzheimer’s, Tanzi and colleagues are now searching for agents that can cross the blood-brain barrier and block it.
(Source: nimh.nih.gov)
Scientists from the University of Southampton have identified the molecular system that contributes to the harmful inflammatory reaction in the brain during neurodegenerative diseases.
An important aspect of chronic neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, Huntington’s or prion disease, is the generation of an innate inflammatory reaction within the brain.
Results from the study open new avenues for the regulation of the inflammatory reaction and provide new insights into the understanding of the biology of microglial cells, which play a leading role in the development and maintenance of this reaction.
Dr Diego Gomez-Nicola, from the CNS Inflammation group at the University of Southampton and lead author of the paper, says: “The understanding of microglial biology during neurodegenerative diseases is crucial for the development of potential therapeutic approaches to control the harmful inflammatory reaction. These potential interventions could modify or arrest neurodegenerative diseases like Alzheimer disease.
“The future potential outcomes of this line of research would be rapidly translated into the clinics of neuropathology, and would improve the quality of life of patients with these diseases.”
Microglial cells multiply during different neurodegenerative conditions, although little is known about to what extent this accounts for the expansion of the microglial population during the development of the disease or how it is regulated.
Writing in The Journal of Neuroscience, scientists from the University of Southampton describe how they used a laboratory model of neurodegeneration (murine prion disease), to understand the brain’s response to microglial proliferation and dissected the molecules regulating this process. They found that signalling through a receptor called CSF1R is a key for the expansion of the microglial population and therefore drugs could target this.
Dr Diego Gomez-Nicola adds: “We have been able to identify that this molecular system is active in human Alzheimer’s disease and variant Creutzfeldt–Jakob disease, pointing to this mechanism being universal for controlling microglial proliferation during neurodegeneration. By means of targeting CSF1R with selective inhibitors we have been able to delay the clinical symptoms of experimental prion disease, also preventing the loss of neurons.”