Archive for the ‘Inflammation’ Category

Almost all injuries, even minor skin scratches, trigger an inflammatory response, which provides protection against invading microbes but also turns on regenerative signals needed for healing and injury repair -- a process that is generally understood but remains mysterious in its particulars.

Writing in the February 25 online issue of Nature, an international team of scientists, headed by researchers at the University of California, San Diego School of Medicine, report finding new links between inflammation and regeneration: signaling pathways that are activated by a receptor protein called gp130. "We found that gp130 is capable of activating several signaling pathways that turn on a number of transcription factors known to have a key role in stem cell biology," said the study's lead author, Koji Taniguchi, MD, PhD, assistant project scientist in the Department of Pharmacology at UC San Diego.

These transcription factors -- specifically STAT3, YAP and Notch -- stimulate the proliferation and survival of normal tissue stem cells, which lead to healing and repair, said senior author Michael Karin, PhD, Distinguished Professor Pharmacology and Pathology and head of UC San Diego's Laboratory of Gene Regulation and Signal Transduction.

"While the work was mainly conducted on a mouse model of intestinal injury, similar to the one that underlies human inflammatory bowel disease (IBD), we provide evidence that the same mechanism may control liver regeneration, which suggests a general role in tissue repair," said Karin.

In addition to explaining a key biomedical phenomenon, the researchers said the findings have important clinical implications for the treatment of IBD and colorectal cancer. The major signal sensed by gp130 is the inflammatory hormone (cytokine) IL-6 and closely related proteins. Expression of IL-6 has been found to be elevated in IBD, both in Crohn's disease and ulcerative colitis, giving rise to the possibility that inhibition of IL-6 binding to its receptor -- a complex between gp130 and a specific IL-6 binding protein -- may ameliorate the pathology of IBD.

But just the opposite has been observed. Drugs that block the binding of IL-6 to its receptor complex actually increase the risk of intestinal perforation and bleeding, making them unsuitable for the treatment of IBD. The new work suggests that IL-6 and the signaling pathways it stimulates are not the cause of IBD, but are part of the natural protective reaction to the initial injury and inflammatory response associated with the onset of IBD.

The Taniguchi and Karin team say it is important that future treatments not interfere with the healing response triggered by IL-6 and gp130. Nonetheless, the same pathways involved in healing and regeneration can go awry and become chronically stimulated in colorectal cancer.

The new work defines several molecular targets suitable for development of new targeted therapies for this very common malignancy -- the third leading cause of cancer-related death, though Karin cautioned that "such treatments should not be combined with conventional and highly toxic anti-cancer drugs whose major side effect is damage and inflammation of the intestinal mucosa, a disease known as mucositis that will only be exacerbated by blocking the regenerative response triggered by IL-6."

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The above story is based on materials provided by University of California, San Diego Health Sciences. The original article was written by Scott LaFee. Note: Materials may be edited for content and length.

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Link between inflammation, tissue regeneration and wound repair response

PUBLIC RELEASE DATE:

6-Nov-2014

Contact: Yixian Zheng zheng@ciwemb.edu 410-246-3032 Carnegie Institution @carnegiescience

Baltimore, MD--As animals age, their immune systems gradually deteriorate, a process called immunosenescence. It is associated with systemic inflammation and chronic inflammatory disorders, as well as with many cancers. The causes underlying this age-associated inflammation, and how it leads to diseases, are poorly understood. New work in Carnegie's Yixian Zheng's lab sheds light on one protein's involvement in suppressing immune responses in aging fruit flies. It is published in Cell.

Insects have an immune organ called the fat body, which is roughly equivalent to the mammalian fat and liver. It is responsible for many immune functions. Zheng and her team--Carnegie's Haiyang Chen and Xiaobin Zheng--found that the fruit fly fat body experiences a great deal of inflammation in aged flies.

These inflamed fly fat bodies then secrete proteins that lead to a reduction in immune response of the gut. This reduction of the gut immune response causes the gut's stem cells to undergo excessive division and inappropriate differentiation, creating a condition called hyperplasia that shares features with the precancerous polyps found in human guts.

Zheng and her team found that the gradual reduction of a protein called lamin-B in the fat bodies of aging flies is the culprit behind fat body inflammation and the resulting hyperplastic gut, all of which falls under the umbrella of immunosenescence.

Lamin-B is part of the lamin family of proteins, which form the major structural component of the material that lines the inside of a cell's nucleus. Lamins have diverse functions, including suppressing gene expression, and they are found in an array of tissues and organs. In humans, diseases caused by mutations in lamins are called laminopathies and include premature aging.

B-type lamins have long been suspected to play a role in gene suppression by binding to segments of DNA. The team's work revealed that when the fruit fly fat body was depleted of lamin-B, the normal suppression of genes involved in the immune response is reversed, just as it would be in response to bacterial infection or injury, but in this case there is no apparent infection or injury. The un-suppressed immune response initiates the inflammation and resulting gut hyperplasia.

"Our findings have implications for mammals as well as for insects, as immune response genes in mammals also are known to have lamins present on them," Zheng explained. "We think that lamin-B might play an evolutionarily conserved role in suppressing inflammatory genes in immune organs in the absence of infection or injury and our work could provide insight into immunosenescence in humans."

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A cause of age-related inflammation found

People with autism spectrum disorder often experience a period of accelerated brain growth after birth. No one knows why, or whether the change is linked to any specific behavioral changes.

A new study by UCLA researchers demonstrates how, in pregnant mice, inflammation, a first line defense of the immune system, can trigger an excessive division of neural stem cells that can cause "overgrowth" in the offspring's brain.

The paper appears Oct. 9 in the online edition of the journal Stem Cell Reports.

"We have now shown that one way maternal inflammation could result in larger brains and, ultimately, autistic behavior, is through the activation of the neural stem cells that reside in the brain of all developing and adult mammals," said Dr. Harley Kornblum, the paper's senior author and a director of the Neural Stem Cell Research Center at UCLA's Semel Institute for Neuroscience and Human Behavior.

In the study, the researchers mimicked environmental factors that could activate the immune system -- such as an infection or an autoimmune disorder -- by injecting a pregnant mouse with a very low dose of lipopolysaccharide, a toxin found in E. coli bacteria. The researchers discovered the toxin caused an excessive production of neural stem cells and enlarged the offspring's' brains.

Neural stem cells become the major types of cells in the brain, including the neurons that process and transmit information and the glial cells that support and protect them.

Notably, the researchers found that mice with enlarged brains also displayed behaviors like those associated with autism in humans. For example, they were less likely to vocalize when they were separated from their mother as pups, were less likely to show interest in interacting with other mice, showed increased levels of anxiety and were more likely to engage in repetitive behaviors like excessive grooming.

Kornblum, who also is a professor of psychiatry, pharmacology and pediatrics at the David Geffen School of Medicine at UCLA, said there are many environmental factors that can activate a pregnant woman's immune system.

"Although it's known that maternal inflammation is a risk factor for some neurodevelopmental disorders such as autism, it's not thought to directly cause them," he said. He noted that autism is clearly a highly heritable disorder, but other, non-genetic factors clearly play a role.

The researchers also found evidence that the brain growth triggered by the immune reaction was even greater in mice with a specific genetic mutation -- a lack of one copy of a tumor suppressor gene called phosphatase and tensin homolog, or PTEN. The PTEN protein normally helps prevent cells from growing and dividing too rapidly. In humans, having an abnormal version of the PTEN gene leads to very large head size or macrocephaly, a condition that also is associated with a high risk for autism.

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Neural stem cell overgrowth, autism-like behavior linked, mice study suggests

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Newswise People with autism spectrum disorder often experience a period of accelerated brain growth after birth. No one knows why, or whether the change is linked to any specific behavioral changes.

A new study by UCLA researchers demonstrates how, in pregnant mice, inflammation, a first line defense of the immune system, can trigger an excessive division of neural stem cells that can cause overgrowth in the offsprings brain.

The paper appears Oct. 9 in the online edition of the journal Stem Cell Reports.

We have now shown that one way maternal inflammation could result in larger brains and, ultimately, autistic behavior, is through the activation of the neural stem cells that reside in the brain of all developing and adult mammals, said Dr. Harley Kornblum, the papers senior author and a director of the Neural Stem Cell Research Center at UCLAs Semel Institute for Neuroscience and Human Behavior.

In the study, the researchers mimicked environmental factors that could activate the immune system such as an infection or an autoimmune disorder by injecting a pregnant mouse with a very low dose of lipopolysaccharide, a toxin found in E. coli bacteria. The researchers discovered the toxin caused an excessive production of neural stem cells and enlarged the offsprings brains.

Neural stem cells become the major types of cells in the brain, including the neurons that process and transmit information and the glial cells that support and protect them.

Notably, the researchers found that mice with enlarged brains also displayed behaviors like those associated with autism in humans. For example, they were less likely to vocalize when they were separated from their mother as pups, were less likely to show interest in interacting with other mice, showed increased levels of anxiety and were more likely to engage in repetitive behaviors like excessive grooming.

Kornblum, who also is a professor of psychiatry, pharmacology and pediatrics at the David Geffen School of Medicine at UCLA, said there are many environmental factors that can activate a pregnant womans immune system.

Excerpt from:
Study Finds Link Between Neural Stem Cell Overgrowth and Autism-Like Behavior in Mice

PUBLIC RELEASE DATE:

9-Oct-2014

Contact: Mark Wheeler mwheeler@mednet.ucla.edu 310-794-2265 University of California - Los Angeles @uclanewsroom

People with autism spectrum disorder often experience a period of accelerated brain growth after birth. No one knows why, or whether the change is linked to any specific behavioral changes.

A new study by UCLA researchers demonstrates how, in pregnant mice, inflammation, a first line defense of the immune system, can trigger an excessive division of neural stem cells that can cause "overgrowth" in the offspring's brain.

The paper appears Oct. 9 in the online edition of the journal Stem Cell Reports.

"We have now shown that one way maternal inflammation could result in larger brains and, ultimately, autistic behavior, is through the activation of the neural stem cells that reside in the brain of all developing and adult mammals," said Dr. Harley Kornblum, the paper's senior author and a director of the Neural Stem Cell Research Center at UCLA's Semel Institute for Neuroscience and Human Behavior.

In the study, the researchers mimicked environmental factors that could activate the immune system such as an infection or an autoimmune disorder by injecting a pregnant mouse with a very low dose of lipopolysaccharide, a toxin found in E. coli bacteria. The researchers discovered the toxin caused an excessive production of neural stem cells and enlarged the offspring's' brains.

Neural stem cells become the major types of cells in the brain, including the neurons that process and transmit information and the glial cells that support and protect them.

Notably, the researchers found that mice with enlarged brains also displayed behaviors like those associated with autism in humans. For example, they were less likely to vocalize when they were separated from their mother as pups, were less likely to show interest in interacting with other mice, showed increased levels of anxiety and were more likely to engage in repetitive behaviors like excessive grooming.

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UCLA study finds link between neural stem cell overgrowth and autism-like behavior in mice

Brain inflammation can rapidly disrupt our ability to retrieve complex memories of similar but distinct experiences, according to UC Irvine neuroscientists Jennifer Czerniawski and John Guzowski.

Their study -- which appears today in The Journal of Neuroscience -- specifically identifies how immune system signaling molecules, called cytokines, impair communication among neurons in the hippocampus, an area of the brain critical for discrimination memory. The findings offer insight into why cognitive deficits occurs in people undergoing chemotherapy and those with autoimmune or neurodegenerative diseases.

Moreover, since cytokines are elevated in the brain in each of these conditions, the work suggests potential therapeutic targets to alleviate memory problems in these patients.

"Our research provides the first link among immune system activation, altered neural circuit function and impaired discrimination memory," said Guzowski, the James L. McGaugh Chair in the Neurobiology of Learning & Memory. "The implications may be beneficial for those who have chronic diseases, such as multiple sclerosis, in which memory loss occurs and even for cancer patients."

What he found interesting is that increased cytokine levels in the hippocampus only affected complex discrimination memory, the type that lets us differentiate among generally similar experiences -- what we did at work or ate at dinner, for example. A simpler form of memory processed by the hippocampus -- which would be akin to remembering where you work -- was not altered by brain inflammation.

In the study, Czerniawski, a UCI postdoctoral scholar, exposed rats to two similar but discernable environments over several days. They received a mild foot shock daily in one, making them apprehensive about entering that specific site. Once the rodents showed that they had learned the difference between the two environments, some were given a low dose of a bacterial agent to induce a neuroinflammatory response, leading to cytokine release in the brain. Those animals were then no longer able to distinguish between the two environments.

Afterward, the researchers explored the activity patterns of neurons -- the primary cell type for information processing -- in the rats' hippocampi using a gene-based cellular imaging method developed in the Guzowski lab. In the rodents that received the bacterial agent (and exhibited memory deterioration), the networks of neurons activated in the two environments were very similar, unlike those in the animals not given the agent (whose memories remained strong). This finding suggests that cytokines impaired recall by disrupting the function of these specific neuron circuits in the hippocampus.

"The cytokines caused the neural network to react as if no learning had taken place," said Guzowski, associate professor of neurobiology & behavior. "The neural circuit activity was back to the pattern seen before learning."

The work may also shed light on a chemotherapy-related mental phenomenon known as "chemo brain," in which cancer patients find it difficult to efficiently process information. UCI neuro-oncologists have found that chemotherapeutic agents destroy stem cells in the brain that would have become neurons for creating and storing memories.

Dr. Daniela Bota, who co-authored that study, is currently collaborating with Guzowski's research group to see if brain inflammation may be another of the underlying causes of "chemo brain" symptoms.

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Brain inflammation dramatically disrupts memory retrieval networks, study finds

Like a line of falling dominos, a cascade of molecular events in the bone marrow produces high levels of inflammation that disrupt normal blood formation and lead to potentially deadly disorders including leukemia, an Indiana University-led research team has reported.

The discovery, published by the journal Cell Stem Cell, points the way to potential new strategies to treat the blood disorders and further illuminates the relationship between inflammation and cancer, said lead investigator Nadia Carlesso, M.D., Ph.D., associate professor of pediatrics at the Indiana University School of Medicine.

Bone marrow includes the cells that produce the body's red and white blood system cells in a process called hematopoiesis. The marrow also provides a support system and "home" for the blood-producing cells called the hematopoietic microenvironment. The new research demonstrates the importance of the hematopoietic microenvironment in the development of a group of potentially deadly diseases called myeloproliferative disorders.

"It has been known for years that there are links between inflammation and cancer, but these studies have been challenged by the lack of genetic models, especially for blood-based malignancies," said Dr. Carlesso, a member of the hematologic malignancy and stem cell biology program within the Wells Center for Pediatric Research at IU.

The researchers focused on what happens when there are abnormally low levels of a molecule called Notch, which plays an important role in the process of blood cell production. Using a genetically modified mouse, they found that the loss of Notch function in the microenvironment causes a chain of molecular events that result in excess production of inflammatory factors.

The high levels of inflammation in the bone marrow were associated with the development of a myeloproliferative disorder in the mice. Myeloproliferative diseases in humans can result in several illnesses caused by overproduction of myeloid cells, which are normally are used to fight infections. These diseases can put patients at risk for heart attack or stroke, and frequently progress into acute leukemia and bone marrow failure, which have fatal outcomes. Unfortunately, there are no effective therapies for the majority of myeloproliferative diseases.

When Dr. Carlesso's team blocked the activity of one of the molecules in this biochemical cascade, the myeloproliferative disorder in the mice was reversed. In addition, elevated levels of the blocked molecule were found in samples from human patients with myeloproliferative disease. These findings suggest that developing drugs that target this inflammatory reaction at different key points could be a promising strategy to limit the development of myeloproliferative disease in humans.

The molecular cascade leading to inflammation was not occurring directly in the bone marrow cells that produce blood cells, but in cells of the bone marrow microenvironment, especially in endothelial cells that line the capillaries -- tiny blood vessels -- inside the bone marrow. This was a key discovery, Dr. Carlesso said.

"This work indicates that we need to target not only the tumor cells, but also the inflammatory microenvironment that surrounds them and may contribute to their generation," she said.

"We believe that this combined strategy will be more effective in preventing myeloproliferative disease progression and transformation in acute leukemias."

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Biochemical cascade causes bone marrow inflammation, leading to serious blood disorders

(2012-08b) Ron Rothenberg - Inflammation, Hormones, Stem Cells Telomeres
W URL at: https://www.youtube.com/watch?v=h6JOZ6i6MBw Update in Preventive/Regenerative Medicine -- Inflammation, Hormones, Stem Cells and Telomeres- by Ron ...

By: Silicon Valley Health Institute

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(2012-08b) Ron Rothenberg - Inflammation, Hormones, Stem Cells & Telomeres - Video

PUBLIC RELEASE DATE:

16-Apr-2014

Contact: Tom Vasich tmvasich@uci.edu 949-824-6455 University of California - Irvine

Irvine, Calif., April 16, 2014 A class of drugs developed to treat immune-related conditions and cancer including one currently in clinical trials for glioblastoma and other tumors eliminates neural inflammation associated with dementia-linked diseases and brain injuries, according to UC Irvine researchers.

In their study, assistant professor of neurobiology & behavior Kim Green and colleagues discovered that the drugs, which can be delivered orally, eradicated microglia, the primary immune cells of the brain. These cells exacerbate many neural diseases, including Alzheimer's and Parkinson's, as well as brain injury.

"Because microglia are implicated in most brain disorders, we feel we've found a novel and broadly applicable therapeutic approach," Green said. "This study presents a new way to not just modulate inflammation in the brain but eliminate it completely, making this a breakthrough option for a range of neuroinflammatory diseases."

The researchers focused on the impact of a class of drugs called CSF1R inhibitors on microglial function. In mouse models, they learned that inhibition led to the removal of virtually all microglia from the adult central nervous system with no ill effects or deficits in behavior or cognition. Because these cells contribute to most brain diseases and can harm or kill neurons the ability to eradicate them is a powerful advance in the treatment of neuroinflammation-linked disorders.

Green said his group tested several selective CSF1R inhibitors that are under investigation as cancer treatments and immune system modulators. Of these compounds, they found the most effective to be a drug called PLX3397, created by Plexxikon Inc., a Berkeley, Calif.-based biotechnology company and member of the Daiichi Sankyo Group. PLX3397 is currently being evaluated in phase one and two clinical trials for multiple cancers, including glioblastoma, melanoma, breast cancer and leukemia.

Crucially, microglial elimination lasted only as long as treatment continued. Withdrawal of inhibitors produced a rapid repopulation of cells that then grew into new microglia, said Green, who's a member of UC Irvine's Institute for Memory Impairments and Neurological Disorders.

This means that eradication of these immune cells is fully reversible, allowing researchers to bring microglia back when desired. Green added that this work is the first to describe a new progenitor/potential stem cell in the central nervous system outside of neurogenesis, a discovery that points to novel opportunities for manipulating microglial populations during disease.

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Cancer drugs block dementia-linked brain inflammation, UCI study finds

A class of drugs developed to treat immune-related conditions and cancer -- including one currently in clinical trials for glioblastoma and other tumors -- eliminates neural inflammation associated with dementia-linked diseases and brain injuries, according to UC Irvine researchers.

In their study, assistant professor of neurobiology & behavior Kim Green and colleagues discovered that the drugs, which can be delivered orally, eradicated microglia, the primary immune cells of the brain. These cells exacerbate many neural diseases, including Alzheimer's and Parkinson's, as well as brain injury.

"Because microglia are implicated in most brain disorders, we feel we've found a novel and broadly applicable therapeutic approach," Green said. "This study presents a new way to not just modulate inflammation in the brain but eliminate it completely, making this a breakthrough option for a range of neuroinflammatory diseases."

The researchers focused on the impact of a class of drugs called CSF1R inhibitors on microglial function. In mouse models, they learned that inhibition led to the removal of virtually all microglia from the adult central nervous system with no ill effects or deficits in behavior or cognition. Because these cells contribute to most brain diseases -- and can harm or kill neurons -- the ability to eradicate them is a powerful advance in the treatment of neuroinflammation-linked disorders.

Green said his group tested several selective CSF1R inhibitors that are under investigation as cancer treatments and immune system modulators. Of these compounds, they found the most effective to be a drug called PLX3397, created by Plexxikon Inc., a Berkeley, Calif.-based biotechnology company and member of the Daiichi Sankyo Group. PLX3397 is currently being evaluated in phase one and two clinical trials for multiple cancers, including glioblastoma, melanoma, breast cancer and leukemia.

Crucially, microglial elimination lasted only as long as treatment continued. Withdrawal of inhibitors produced a rapid repopulation of cells that then grew into new microglia, said Green, who's a member of UC Irvine's Institute for Memory Impairments and Neurological Disorders.

This means that eradication of these immune cells is fully reversible, allowing researchers to bring microglia back when desired. Green added that this work is the first to describe a new progenitor/potential stem cell in the central nervous system outside of neurogenesis, a discovery that points to novel opportunities for manipulating microglial populations during disease.

Study results appear in today's issue of Neuron.

Story Source:

The above story is based on materials provided by University of California - Irvine. Note: Materials may be edited for content and length.

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Cancer drugs block dementia-linked brain inflammation, study finds