Environmental Factor

March 2011


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Intramural papers of the month

By Ritu Rana, Matt Goad, and Robin Arnette
March 2011

Uncontrolled neuroinflammation drives progressive neurodegenerative disorders

Researchers at NIEHS reported that persistent neuroinflammation caused by uncontrolled activation of brain immune cells known as microglia, leads to the gradual loss of neurons in Parkinson's disease.

Previous studies had shown that Parkinson's disease is a progressive neurodegenerative disorder characterized by chronic neuroinflammation and the gradual loss of dopamine neurons. The authors used three different neurotoxins (1-methyl-4-phenylpyridinium, lipopolysaccharide, and rotenone) to mimic Parkinson's disease models. They found that though these toxins were sufficient to generate acute neurotoxicity in neuron-enriched cultures, microglia are required for the progressive neurodegeneration.

Mechanistic studies showed that high-mobility group box 1 (HMGB1) protein, released by activated microglia and damaged neurons, interacts with macrophage antigen complex 1(Mac1) present on microglia and activates the nuclear factor-kappaBeta (NF-κB) pathway. The activated NF-κB pathway produces various inflammatory factors contributing to chronic neuroinflammation. HMGB1-Mac1 interaction also activates NADPH oxidase and inducible nitric oxide synthase (iNOS) enzymes releasing many reactive free radicals causing oxidative insult to the neurons.

Researchers further showed that HMGB1 fails to activate NF-κB and NADPH oxidase signaling pathways in Mac1-deficient microglia, suggesting Mac1 is a potential therapeutic target for the treatment of Parkinson's disease.

Citation: Gao HM, Zhou H, Zhang F, Wilson BC, Kam W, Hong JS.(http://www.ncbi.nlm.nih.gov/pubmed/21248133) Exit NIEHS 2011. HMGB1 acts on microglia Mac1 to mediate chronic neuroinflammation that drives progressive neurodegeneration. J Neurosci 31(3):1081-1092.

Interleukin-10 protects against ozone-induced lung inflammation

A collaborative study between NIEHS, the University of North Carolina, and Michigan State University demonstrates the mechanism by which Interleukin-10 (IL-10) protects lung inflammation from ozone (O3)-exposure. The study identified some potential pathways and their downstream molecular events that are involved in anti-inflammatory effect of IL-10 against ozone toxicity.

Researchers compared wild-type and IL10-deficient mice for their lung inflammatory response against O3 assault and found that loss of IL10 enhanced O3-induced inflammation and injury to the lung. Results showed that O3 exposure increased infiltrating neutrophils and enhanced cellular proliferation in centriacinar regions of the lung in IL-10 null mice as compared to wild-type. Researchers suggested that IL-10 provides lung protection from O3 by modulating nuclear activity of nuclear factor-κB (NF-κB) and expression of inflammatory mediators such as macrophage CD86 and macrophage inflammatory protein 2 (MIP2). Higher activity and expression of inflammatory mediators were observed in IL10-deficient mice upon O3 exposure.

Furthermore, using microarray and pathway analyses, scientists identified three IL-10 affiliated pathways that are involved in IL10-mediated anti-inflammatory activity. Researchers also found novel genes that may be potentially contributing to O3 -mediated pulmonary inflammation and could serve as potential therapeutic targets against O3-induced pathogenesis.

Citation: Backus GS, Howden R, Fostel J, Bauer AK, Cho HY, Marzec J, Peden DB, Kleeberger SR.(http://www.ncbi.nlm.nih.gov/pubmed/20826374) Exit NIEHS 2010. Protective role of interleukin-10 in ozone-induced pulmonary inflammation. Environ Health Perspect 118(12):1721-1727.

Mutations resulting from subtle chemical "trickery"

Using X-ray crystallography, NIEHS researchers have determined that human DNA polymerase can incorporate a guanine-thymine (G•T) mismatch during DNA synthesis that is structurally similar to the correct adenine-thymine (A•T) base pair. The results, published in a February 2011 issue of PNAS, are the first evidence of DNA bases forming mismatches with correct Watson-Crick geometry, which can potentially lead to mutations. In addition, the typical sources of environmental stress on DNA, such as exposure to UV light or chemical toxins, don't cause these mutations. They happen spontaneously.

James Watson and Francis Crick first proposed the spontaneous base substitution mutation theory in their Nature papers describing the structure of the DNA double helix in 1953. The hypothesis was difficult to test, so evidence supporting it remained elusive for 58 years. Because the authors were able to study DNA at the atomic level, they were able to provide support for the idea.

The investigators assert that understanding how a DNA polymerase generates mutations may not only help scientists discern the cause of disease, but also may improve drug design since DNA polymerases commonly serve as targets of pharmaceutical agents.

Citation: Bebenek K, Pedersen LC, Kunkel TA.(http://www.ncbi.nlm.nih.gov/pubmed/21233421) Exit NIEHS 2011. Replication infidelity via a mismatch with Watson-Crick geometry. Proc Natl Acad Sci U S A 108(5):1862-1867. Story (http://www.niehs.nih.gov/news/newsletter/2011/february/science-mismatch/)

Categorizing heterogeneous myositis syndromes by phenotype

In a recent issue of JAMA, NIEHS researchers argue for the systematic grouping of idiopathic inflammatory myopathies also known as myositis syndromes.

The research team concluded that understanding and categorizing the many mutually exclusive and stable myositis phenotypes will aid in deciphering the mechanisms by which these conditions arise in humans, and help in interpreting and anticipating care. The authors encourage incorporation of phenotype status into future investigations of pathogenesis and therapy.

Myositis syndromes are systemic autoimmune diseases defined by chronic muscle weakness and inflammation of unknown etiology, and result in significant morbidity and mortality. The most common forms are polymyositis, dermatomyositis, and inclusion body myositis.

Citation: Rider LG, Miller FW.(http://www.ncbi.nlm.nih.gov/pubmed/21224460) Exit NIEHS 2011. Deciphering the clinical presentations, pathogenesis, and treatment of the idiopathic inflammatory myopathies. JAMA 305(2):183-190. Story (http://www.niehs.nih.gov/news/newsletter/2011/february/science-niehs/)

(Ritu Rana, Ph.D., is a visiting fellow in the NIEHS Laboratory of Toxicology and Pharmacology Human Metabolism Group. Matt Goad is a contract writer with the NIEHS Office of Communications and Public Liaison.)



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