Microglia – The immune Cells of the Brain
It is heartbreaking to see someone you love suffer from mental illness and/or neurodegenerative disease, e.g. Parkinson’s disease. Doctors have traditionally treated mental illness with drugs to alter the brain’s chemistry in case of mental illness or pharmaceuticals with respect to Alzheimer, Parkinson and other neurodegenerative diseases. Research has pointed towards the role of Microglia and their pro-inflammatory cytokines leading to neurobehavioral changes (mental illness) as well as neurodegenerative diseases. Here we will discuss Microglia and their role as brain immune cells in brain dysfunctions.
What are Microglia and their immune functions in the brain? Microglia are immune system cells that originate in bone marrow and migrate from blood to the brain acting as the first and main form of active immune defense in the central nervous system (CNS). They defend the brain and spinal cord, constantly excavating the CNS and attacking and engulfing infectious agents. In this process they release pro-inflammatory cytokines that can lead to inflammation of the brain and death of neurons. Their normal activity is the repair of damage caused by foreign insult (traumatic brain injury, toxins, microorganisms, viruses). However, in the disease states associated with activation of the microglia they release cytokines, chemokines, hydrogen peroxide and nitrous oxide (latter two cause free radical formation). The cytokines and chemokines attract lymphocytes, neutrophils and macrophages from the blood into the brain or spinal cord. In the activated state these compounds cause destruction of myelin and death of neurons. I will only cover some of the disease states. All the reader needs to perform is to enter entrez pubmed and search the National Library of Medicine.
Macrophages, Cytokines and Chemokines in CNS Regulation and Pathology
Block ML, Calderon-Garciduenas L. 2009. Air pollution: Mechanisms of neuroinflammation and CNS Disease. Trends Neurosci 32:506-16.
D’Mello C, Le T, Swain MG. 2009. Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factor α signaling during peripheral organ inflammation. Neurobiol Dis 29:2089-2102.
Laskin DL. 2009. Macrophages and inflammatory mediators in chemical toxicity: A battle of forces. Chem Res Toxicol 22:1376-85.
Neumann H, Kotter MR, Franklin RJM. 2009. Debris clearance by microglia: an essential link between degeneration and regeneration. Brain 132:288-295.
Cunningham C, Campion S, Lunnon K, Murray CL, et al. 2009. Systemic inflammation induces acute behavior and cognitive changes and accelerates neurodegenerative disease. Biol Psychiatry 65:304-12.
Miller AH, Maletic V, Raison CL. 2008. Inflammation and its discontents: The role of cytokines in the pathophysiology of major depression. Biol Psychiatry 65:732-41.
De Hass AH, van Weering HRJ, de Jong EK, Boddeke HWGM, Biber KPH. 2007 Neuronal chemokines: Versatile messengers in central nervous system interaction. Mol Neurobiol 36:137-52.
Abbadie C, Bhangoo S, De Koninck Y, Malcangio M, Melik-Parsadaniantz S, White FA 2009 Chemokines in pain mechanisms. Bran Res 60:125-34.
Callewaere C, Banisadr B, Rostene W, Melik-Parsadaniantz S 2007 Chemokines and chemokine receptors in the brain: Implication in neuroendocrine regulation. J Mol Endocrinol 38:355-63.
Liu B, Hong JS. 2002. Role of microglia in inflammation-mediated neurodegenerative diseases: Mechanisms and strategies for therapeutic intervention. J Pharmacol Exper Therap 304:1-7.
Alzheimer’s Disease: Alzheimer’s disease is characterized by the deposition of amyloid-β (Aβ) plaques in the brain parenchnyma and neurofibrillary tangles within neurons. Its neurodegenerative conditons are characterized by chronic neuroinflammation. Currently, questions still arise as whether the inflammation is an underlying cause or a resulting condition of AD. Nevertheless, it is important to recognize that chronic inflammation is present and therefore the disease is listed in this section of brain function and inflammation. Contribution to of toxic exposure as either a cause or exacerbation of AD cannot be ruled out.
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Walker DG, Link J, Lue LF, Daising-Hernandez JE, Boyes BE. 2010 Gene expression changes by amyloid beta-peptide stimulated human postmortem brain microglia identify activation of multiple inflammatory processes. J Leukoc Biol 79:596-610.
Mandrekar-Colucci S, Landreth GE 2010 Microglia and inflammation in Alzheimer’s disease. CNS Neurol Disord Drug Targets. 9:156-67.
Heneka MG, Nadrignyh F, Regen T, Martinez Hernandez A et al. 2007. Locus cerulus controls Alzheimer’s disease pathology by modulating microglial functions through Norepinephrine. PNAS 107:6058-63.
Streit W. 2010. Microglial activation and neuroinflammation in Alzheimer’s disease: a critical examination of the past. Frontier Aging Neurosci June 3 2:22.
Krause DL, Muller N. 2010. Neuroinflammation, Microglia and implications for anti-inflammatory treatment in Alzheimer’s disease. Int J Alzheimer’s Dis. June 10.pii73208.
Neurodegeneration: The papers below discuss the role of microglia and their pro-inflammatory cytokines and their role in neurodegenerative diseases. Some of the below references are repeated purposefully.
Neumann H, Kotter MR, Franklin RJM. 2009 Debris clearance by microglia: an essential link between degeneration and regeneration. Brain: 132:288-95.
Okum E, Griffioen KJ, Lathia JD, Tang SG, Mattson MP, Arumugam TV. 2009 Toll-like receptors in neurodegneration. Brain Res Rev 59:278-92.
Whitney NP, Eidem TM, Pen H, Huang Y, Zheng JC. 2009 Inflammation mediates varying effects on neurogenesis: Relevance to pathogenesis of brain injury and neurodegenerative disorders. J Neurochem 108:1343-59.
Griffin WST. 2006 Inflammation and neurodegenerative diseases. Am J Clin Nutr 83(suppl):470S-4S.
Liu B, Hong J-S. 2003. Role of microglia in inflammation-mediated neurodegenerative diseases: Mechanisms and strategies for therapeutic intervention. J Pharmacol Exper Therap 304:1-7.
Endotoxins (LPS), Viruses, Bacteria, Toxins and Neuroinflammation
Qin L, Wu X, Block ML, Lie Y, Breese GR, et al. 2007 Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55:453-62.
Takahashi K, Funata N, Ikuta F, Sato S. 2008. Neuronal apoptosis and inflammatory responses in the central nervous system of a rabbit treated with Shiga toxin-2. J Neuroinflammation 21:5-11.
Li B, Gao HM, Hong JS. 2003 Parkinson’s disease and exposure to infectious agents and pesticides and the occurrence of brain injuries: role of neuroinflammation. Environ Health Perspec 111:1065-73.
Qin L, He J, Hanes RN, Pluzarev O, Hong JS, Crews FT. 2008. Increased systemic and brain cytokine production and neuroinflammation by endotoxin following alcohol treatment. J Neuroinflammation 18:5-10.
Mattsson N, Bremell D, Anckarsater B, Blenow K, Ankarsater H, et al. 2010. Neuroinflammation in Lyme neuroborreliosis affects amyloid metabolism. BMC NerureolJuly 22;10:51.
Contini C, Seraceni S, Cultrera R, Castellazzi M, Granieri E, Fainardi E. 202-. Chlamydophila pneumoniae infection and its role in neurological disorders. Interdiscip Perspect Infect Dis 22020:273573 [Epub].
Jang H, Boltz D, Sturm-Ramizez K, Shepherd KR, Kiao Y, Webser R. Smeyne J. 2009. Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neuro-degeneration. Proc Nat Acad Sci USA. Aug 28:206(33):20463. Epub Aug 10.
Malaeg S, Dammann O. 200. Fetal inflammatory response and brain injury in the pre term newborn. J Child Neurol 24:119-26.
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Mouse Study on Neuroinflammation Treatment
A News Release
SALT LAKE CITY — It is heartbreaking to see someone you love suffer from mental illness. Now a famous Utah scientist says he’s made a big breakthrough in the research to find a cure.
Doctors have traditionally treated mental illness with drugs to alter the brain’s chemistry, but the University of Utah’s Nobel Prize-winning geneticist Dr. Mario Capecchi tried a new approach on a lab mouse. He treated the animal for the illness the same way you would many other illnesses — by treating its immune system.
Microglia are immune system cells that originate in bone marrow and migrate from blood to the brain acting as the first and main form of active immune defense in the central nervous system (CNS) defending the brain and spinal cord, constantly excavating the CNS and attacking and engulfing infectious agents.
Capecchi says compulsive behavior doesn’t just affect people. In fact, he had a lab mouse who was suffering from the condition trichotillomania, where one pulls their own hair out. Scientists say it was the mouse that led to the ground-breaking discovery as they found a way to cure him.
“There’s a direct correlation, in essence, between the immune system and behavior,” Capecchi says.
He says scientists have known for years that there is a connection between behavior and the immune system, but they didn’t quite understand it. Now he and his team have discovered it all has to do with a tiny cell called microglia.
Microglia were believed to be “scavenger cells” that would clean up damage in the brain, but Capecchi says the cells are much more powerful than they were letting on.
“What we’re saying is microglia are much more sophisticated and are actually controlling behavior, and they have to do it by interacting the nerve cells in your brain,” Capecchi says.
Before and after pictures of the mouse treated for trichotillomania. – Courtesy Shau-Kwaun Chen, the University of Utah They found people and animals afflicted with behavior disorders have deformed microglia cells. So, instead of treating mental illness the way doctors traditionally have –
with medication to alter brain chemistry — they tried a new approach by treating the immune system. The researchers used a procedure on the mouse that’s commonly practiced on cancer patients — a bone marrow transplant.
“That cured the disease permanently,” Capecchi says. “All the hair grew back, all the lesions were healed, and the mouse no longer removes the body hair.”
Capecchi says this new discovery could lead to cures for mental disorders from autism to schizophrenia.
“The book is just opened, and so there are many, many possibilities; and hopefully not only will we pursue it, but also hopefully it will interest other researchers, other investigators, to pursue similar experiments,” Capecchi says.
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News Release Regarding the Mouse Study Mentioned Above
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Cryptococcus neoformans is endemic to the dry desert climates of California and Arizona. It can cause serious infections in animals and humans. Now comes a new species, C. gattii, which has been infecting animals and humans in the N.W. Region. C. gattii, unlike C. Neoformans, thrives in moist environments.
Health care professionals in Oregon and Washington are being asked to watch out for a deadly new strain of airborne fungus. This new type of fungus is infecting otherwise healthy people. Typically, fungal diseases strike people with weak immune systems, but this strain is different.
Researchers at Duke University are analyzing 21 recent cases of the disease and they all broke out right here in the Northwest. The fungus is called Cryptococcus gattii and these recent cases are a new more deadly strain. Out of the 21 cases, 6 of the patients died.
“It can simulate some other common type of pneumonia’s,” said Providence Portland MD John Heffner. “Instead of anti-biotics you need to treat this with anti-fungal therapy that we usually never use for pneumonia.”
The fungus can be treated, but not prevented. Right now there is no vaccine. Symptoms of the fungal disease include a chronic cough, sharp chest pain, shortness of breath, headache, fever and weight loss. Human cases have been identified (see photos below)
Scientists say the disease has also struck dozens of dogs and cats in Oregon and Washington. Cryptococcus gattii has also been spotted in bottle nose dolphins off the coast of California.
“The animals are at risk for getting it, but it comes somewhere from the environment and we haven’t been able to chase down where it comes from,” said Dr. Heffner.It doesn’t appear to be very infectious from animals to humans. Public health officials are on watch. Researchers say overall it’s still a low threat, however as the number of cases increase, so will the interest. The photos below are published by the CDC.
Ulcerated Skin Lesion
Nasal Granuloma – Cat
Western Distribution and Mode of Infection
Cell – 575-937-1150