Microglia are the residing phagocytic immune cell within the central nervous system (CNS), that are important in innate and adaptive immunity [1, 2]. They have many similar characteristics to macrophages and dendritic cells. However, microglia are also suggested that they help support the brain much like astroglia and oligodendroglia [2]. Microglia are derived from the hematopoeitic lineage and enter the brain as an immature cell. The major function of microglia is to clear debris from apoptotic cells but they also detect and destroy possible pathogens. There are several ways to activate microglia. Direct activation is where microglia are stimulated directly, such as when lipipolysaccride (LPS) from bacteria cell wall binds to Toll-like receptors (TLR) on the microglia. Indirect activation is when a neuron is damaged via a neurotoxin and the protein from the destroyed cell activates microglia. There is also a mixed pathway approach to activating microglia, example HIV gp 120 and prions, they act as a direct neurotoxin and directly stimulant microglia. Once activated, microglia change morphology (they become amoeboid cell) and there is an up regulation of cellular receptors, like MHC class I and MCH class II, TLR, mannose receptors, and complement receptors [1, 2]. Activated microglia secrete several proinflammatory cytokines (TNFα and IL-1β), neurotoxins, reactive oxygen species (ROS) and reactive nitrogen species (RNS) which destroy the infection along with surrounding neurons.
Many studies has investigated the role of microglia in neurodegenerative diseases, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), multiple sclerosis (MS), HIV syndrome dementia, and prion relative disease. In AD brains, reactive microglia where found in plagues in the cortical region. A look closer at post-mortem PD brains revealed an increased levels of proinflammatory cytokines and oxidative stress indicating activation of microglia within the substantia nigra (SN).
It is suggested that some of the secreted factors from microglia contributing to neurodegeneration. One study found that the combined affect of TNFα and IL-1β induced neurodegeneration. Within a rat model, 1-2 weeks after LPS introduction microglia were at maximum activation and degeneration of neurons occurred at 3-4 weeks. In a different study it was found that a single injected of a “cytokine cocktail” (TNFα, IL-1β and IFNγ) into the SN was sufficient to cause neural degeneration. It was also demonstrated, in vivo, that the free radicals that where produced by activated microglia where the major contributor to neurodegeneration. These studies concluded that activation of microglia induced by LPS can cause inflammation mediated neurodegeneration [1]. There is on going research on the role of activated microglia and neurodegenerative disease.
1. Bin Liu and Jau-Shyong Hong. Role of Microglia in Inflammation-mediated Neurodegenerative Disease: Mechanisms and Strategies for Therpeutic Intervention. J. of Pharmacology and Experimental Therapeutics. 304(1) 1-7. 2003.
2. Rock, R. Bryan et al. Role of Microglia in Central Nervous System Infections. Clinical Microbiology Reviews. 17(4) 942-964. 2004.
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Did you come across if LPS is permeable to the blood brain barrier?
And I've always wondered how HIV dimentia arises; that is, how do infected T cells get into the brain to activate the microglia?
Seems like the studies that introduced the 'cytokine cocktail' directly into the SN would be damaging the blood brain barrier which would allow macrophages and dendritic cells (which the meninges are full of) to get into the brain parenchyma. A lot of these kinds of studies I've read don't take into consideration the blood brain barrier integrity or if they do, labs acquire different results.
Any ideas on the above questions?
This article provides a readable review of what is known about HIV dementia including sections on `neuroinvasion by HIV' and 'chemokines and their receptors in the brain':
Gonzalez-Scarano F and Martin-Garcia J. The neuropathogenesis of AIDS. Nature Reviews | Immunology 2005; 5:69-81.
Those are very interesting questions. Within the reviews I read there was not direct discussion if LPS is permeable to the blood brain barrier. However, to my understanding, some bacterial infection causes the blood brain barrier to become leaky, therefore the infection can enter and affect the brain.
I am interested in how HIV dementia arises as well. Again in the reviews I read there was talk about the fact that microglia can get infected by HIV but I was not clear on how HIV infection affected the brain. If I come across anything I will let you know.
As for the study that introduced the "cytokine cocktail”, you are correct. The injection would damage the blood brain barrier not to mention the neurons directly. So the question was did the "cytokine cocktail" alone cause neurodegeration or was it inflammation from the injection, or where microbes introduced through the injection site because rodents are not sterile, the article did not address these questions but they are valid questions.
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