Tag: inflammation

Categories : Immune System NeurologyTags :

Study Reveals How The Brain Detects and Regulates Inflammation

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Source: CC0

A study published in the journal Neuron has revealed the existence of a circuit in the brain that senses and regulates the anti-inflammatory response, including the triggering of behaviours associated with sickness and releasing cortisone, a potent negative regulator of immune responses. This circuit embodies a two-way connection between the brain and immune system.

Whenever infections or injuries occur, the immune system is triggered to control the infection and repair damaged tissue. This process involves the release of pro-inflammatory mediators that inform the brain of the body’s immune status and coordinate the immune response. In response to this signal, the brain sets off a complex reaction known as ‘sickness behaviour’ whose purpose is to reassign energy to the body’s different systems. This state is associated with behavioural changes including social avoidance and lethargy, metabolic adjustments such as fever and loss of appetite, and the release of hormones such as cortisone, to increase resistance to infection while also regulating immune responses.

In this study, a multidisciplinary group consisting of neurobiologists and immunologists from the Institut Pasteur, Inserm and the CNRS discovered a novel circuit used by the brain to measure inflammation levels in the blood and, in response to this, regulate inflammation. A region of the brainstem known as the vagal complex directly detects levels and types of inflammatory hormones in the bloodstream. This information is then relayed to neurons in another region of the brainstem called the parabrachial nucleus, which also receives information related to pain and certain aversive or traumatic memories. In turn, these neurons activate neurons in the hypothalamus leading to a rapid increase in cortisone in the blood.

The scientists used state-of-the-art neuroscience approaches to identify this circuit, which enabled them to individually observe the neurons involved during inflammation. The experts observed how the activity of specific neurons in the parabrachial nucleus could regulate the production of white blood cells involved in the immune response. “This research demonstrates that neural activity in the brain alone can have a powerful effect on the development of immune responses during infection or injury. It therefore provides a clear example of the powerful two-way connection between the body and brain. It also fuels our ambition to discover the impact of our brain on the way we interact with microbes, fight off pathogens and heal wounds,” explains Gérard Eberl, Head of the Institut Pasteur’s Microenvironment and Immunity Unit.

The discovery of this circuit opens up new opportunities for research that will jointly contribute to the fields of neurobiology and immunology: “This study gives us additional tools to better understand the impact of systemic inflammation on our brain, mood and on certain neurodegenerative processes,” adds Gabriel Lepousez, a neurobiologist in the Perception and Memory Unit (Institut Pasteur/CNRS).

Given the established role of the parabrachial nucleus in aversive memory processes, potential infectious threats could be averted if this circuit is reactivated by the memory of past inflammatory or aversive experiences. Drawing on this neuro-immune communication, the immune system could therefore benefit from the brain’s ability to predict and anticipate threats in our environment.

Source: Institut Pasteur

Categories : Diseases, Syndromes and Conditions Immune SystemTags :

Training Cells to Fight Both Chronic Inflammatory and Infectious Diseases

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T cell
Scanning Electron Micrograph image of a human T cell. Credit: NIH/NIAID

Researchers from the University of Queensland have identified a pathway in cells that could be used to reprogram the body’s immune system to fight back against both chronic inflammatory and infectious diseases such as E. Coli.

Reporting their findings in the open-access journal PNAS, Dr Kaustav Das Gupta and Professor Matt Sweet found that a glucose-derived molecule in immune cells can both stop bacteria growing and dampen inflammatory responses.

According to Dr Das Gupta, the discovery is a critical step towards future therapeutics that train immune cells.

“The effects of this molecule called ribulose-5-phosphate on bacteria are striking – it can cooperate with other immune factors to stop disease-causing strains of the E. coli bacteria from growing,” Dr Das Gupta said.

“It also reprograms the immune system to switch off destructive inflammation, which contributes to both life-threatening infectious diseases such as sepsis as well as chronic inflammatory diseases like respiratory diseases, chronic liver disease, inflammatory bowel disease, rheumatoid arthritis, heart disease, stroke, diabetes and dementia.”

The research was carried out on a strain of E. coli bacteria, responsible for 80% of urinary tract infections and also a common cause of sepsis. Pre-clinical trials confirmed the role of this pathway in controlling bacterial infections.

Professor Sweet said that human cells were also used to demonstrate that ribulose-5-phosphate reduces the production of molecules that drive chronic inflammatory diseases.

“Host-directed therapies which train our immune systems to fight infections, will become increasingly important as more types of bacteria become resistant to known antibiotics,” Professor Sweet said.

“A bonus is that this strategy also switches off destructive inflammation, which gives it the potential to combat chronic disease.

“By boosting the immune pathway that generates ribulose-5-phosphate, we may be able to give the body the power to fight back against inflammatory and infectious diseases – not one, but two of the major global challenges for human health.”

Many current anti-inflammatory therapies target proteins on the outside of cells but because this pathway occurs inside cells, the researchers devised a new approach to target the pathway using mRNA technology.

Source: University of Queensland

Categories : GastrointestinalTags :

Pain-sensing Neurons Protect the Gut from Damage

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Photo by Andrea Piacquadio on Pexels

Neurons that sense pain protect the gut from inflammation and associated tissue damage by regulating the microbial community living in the intestines, according to a study from Weill Cornell Medicine researchers.

The study, published in Cell, found in a preclinical model that pain-sensing neurons in the gut secrete a molecule called substance P, which appears to protect against gut inflammation and related tissue damage by boosting the population of beneficial microbes in the gut. The researchers also found that these pain-sensing nerves are diminished in number, with significant disruptions to their pain-signaling genes, in people who have inflammatory bowel disease (IBD).

“These findings reshape our thinking about chronic inflammatory disease, and open up a whole new approach to therapeutic intervention,” said study senior author Dr David Artis at Weill Cornell Medicine.

The study’s first author, DrWen Zhang, added: “Defining a previously unknown sensory function for these specific neurons in influencing the microbiota adds a new level of understanding to host-microbiota interactions.”

IBD covers two distinct disorders, Crohn’s disease and ulcerative colitis. It is typically treated with drugs that directly target elements of the immune system. Scientists now appreciate that gut-dwelling bacteria and other microbes also help regulate gut inflammation.

As Dr Artis’s laboratory and others have shown in recent years, the nervous system, which is ‘wired’ into most organs, appears to be yet another powerful regulator of the immune system at the body’s barrier surfaces. In the new study, Dr Artis and his team specifically examined pain neurons that innervate the gut.

These gut-innervating pain neurons, whose cell bodies sit in the lower spine, express a surface protein called TRPV1, which serves as a receptor for pain-related signals. TRPV1 can be activated by high heat, acid, and the chili-pepper compound capsaicin, for example – and the brain translates this activation into a sense of burning pain. The researchers found that silencing these TRPV1 receptors in gut nerves, or deleting TRPV1-expressing neurons, led to much worse inflammation and tissue damage in IBD mouse models, whereas activating the receptors had a protective effect.

The investigators observed that the worsened inflammation and tissue damage in TRPV1-blocked mice were associated with changes in the relative populations of different species of gut bacteria. When this altered bacterial population was transplanted into normal mice, it caused the same worsened susceptibility to inflammation and damage. By contrast, broad-spectrum antibiotic treatment could reverse this susceptibility even in TRPV1-blocked mice. This result demonstrated that TRPV1-expressing nerves protect the gut mainly by helping to maintain a healthy gut microbe population.

The scientists found strong evidence that a large part of this microbe-influencing effect of TRPV1-expressing nerves comes from a molecule the nerves secrete called substance P – which they observed could reverse, on its own, most of the harmful effects of blocking TRPV1. Experiments also suggested that the signaling between neurons and microbes was two-way – some bacterial species could activate TRPV1-expressing nerves to get them to produce more substance P.

To confirm the relevance to humans, the researchers examined gut tissue from IBD patients, and found abnormal TRPV1 and substance P gene activity as well as fewer signs of TRPV1 nerves overall.

“These patients had disrupted pain-sensing nerves, which may have contributed to their chronic inflammation,” Dr Zhang said.

Precisely how substance P exerts its effects on the gut microbe population, and how these microbes “talk back,” are questions that the researchers are now trying to answer in ongoing studies. But the results so far suggest that the next generation of anti-inflammatory drugs for IBD and other disorders could be compounds that target the nervous system.

“A lot of current anti-inflammatory drugs work in only some patients, and pharma companies really haven’t known why,” Dr Artis said. “Maybe it’s because, when it comes to chronic inflammation, we’ve been seeing only some of the picture – and now the rest, including the role of the nervous system, is starting to come into focus.”

Source: Weill Cornell Medicine

Categories : Diseases, Syndromes and ConditionsTags :

Chronic Inflammation Link to Low Vitamin D Explains Some Controversies

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Vitamin D pills
Photo by Michele Blackwell on Unsplash

New genetic research shows a direct link between low vitamin D levels and high levels of inflammation, providing an important biomarker to identify people at higher risk of or severity of chronic illnesses with an inflammatory component, such as type 2 diabetes. The findings, published in the International Journal of Epidemiology, also helps to settle some of the controversies surrounding the ‘sunshine vitamin’.

The study drew on genetic data for 294 970 participants in the UK Biobank, using Mendelian randomisation to show the association between vitamin D and C-reactive protein levels, an indicator of inflammation.

University of South Australia’s Dr Ang Zhou, the study’s lead researcher, said that the findings suggest that boosting vitamin D in people with a deficiency may reduce chronic inflammation.

“This study examined vitamin D and C-reactive proteins and found a one-way relationship between low levels of vitamin D and high levels of C-reactive protein, expressed as inflammation.

“Boosting vitamin D in people with deficiencies may reduce chronic inflammation, helping them avoid a number of related diseases.”

The study also raises the possibility that having adequate vitamin D concentrations may mitigate complications arising from obesity and reduce the risk or severity of chronic illnesses with an inflammatory component, such as CVDs, diabetes, and autoimmune diseases.

Senior investigator and Director of UniSA’s Australian Centre for Precision Health, Professor Elina Hyppönen, said that these results offer an explanation for some of the controversies in reported associations with vitamin D.

“We have repeatedly seen evidence for health benefits for increasing vitamin D concentrations in individuals with very low levels, while for others, there appears to be little to no benefit.” Prof Hyppönen said.

“These findings highlight the importance of avoiding clinical vitamin D deficiency, and provide further evidence for the wide-ranging effects of hormonal vitamin D.”

Source: University of South Australia

Categories : Metabolic DisordersTags :

Just Looking at a Meal Triggers Inflammation

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A hamburger
Photo by Ilya Mashkov on Unsplash

Insulin is released just by the sight and smell of a meal, but now, researchers report in Cell Metabolism that this insulin release depends on a short-term inflammatory response that takes place in these circumstances. In overweight individuals, however, this inflammatory response is so excessive that it can impair insulin secretion.

Even the anticipation of a forthcoming meal triggers a series of responses in the body. Insulin is released in this neurally mediated (or cephalic) phase of insulin secretion.

Meal stimulates immune defence

Until now, it was unclear how the sensory perception of a meal generated a signal to the pancreas to ramp up insulin production. Now, researchers from the University of Basel and University Hospital Basel have identified an important piece of the puzzle: an inflammatory factor known as interleukin 1 beta (IL1B), which is also involved in the immune response to pathogens or in tissue damage.

“The fact that this inflammatory factor is responsible for a considerable proportion of normal insulin secretion in healthy individuals is surprising, because it’s also involved in the development of type 2 diabetes,” explained study leader Professor Marc Donath from the Department of Biomedicine and the Clinic of Endocrinology.

Chronic inflammation damaging the insulin-producing cells of the pancreas is one of the causes of type 2 diabetes. This is another situation in which IL1B plays a key role – in this case, it is produced and secreted in excessively large quantities. Thus, researchers are investigating whether inhibiting IL1B could be a treatment for diabetes.

Short-lived inflammatory response

Circumstances are different when it comes to neurally mediated insulin secretion: “The smell and sight of a meal stimulate specific immune cells in the brain known as the microglia,” said study author Dr Sophia Wiedemann, resident physician for internal medicine. “These cells briefly secrete IL1B, which in turn affects the autonomic nervous system via the vagus nerve.” This system then relays the signal to the pancreas.

In the case of morbid obesity, however, this neurally mediated phase of insulin secretion is disrupted. Specifically, by the initial excessive inflammatory response, as explained by doctoral candidate Kelly Trimigliozzi, who carried out the main part of the study in collaboration with Dr Wiedemann.

“Our results indicate that IL1B plays an important role in linking up sensory information such as the sight and smell of a meal with subsequent neurally mediated insulin secretion – and in regulating this connection,” Prof Marc Donath said.

Source: EurekAlert!

Categories : Immune System Injury & TraumaTags :

Researchers Identify a Key Regulatory Mechanism in Inflammation

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Firefighter
Source: Pixabay CC0

A newly published study has identified a key regulatory mechanism in inflammation that may lead to new targets for resolving that inflammation –and the inflammation of patients with sepsis, cancer and COVID.

In the journal PNAS, scientists reported their discovery of a regulatory pathway for immune response after infection or injury, such as burns. Dysregulation of this pathway could differentiate those who are at risk of fatal sepsis or help identify targets to resolve this unregulated inflammation.

“We are very excited about the findings in this paper and the far-reaching impacts it could have on understanding a key regulatory step in the immune response,” said co-lead author Cindy McReynolds, who holds a doctorate in pharmacology and toxicology.

In a rodent model, the research team found that the metabolites of linoleic acid formed by the enzyme, soluble epoxide hydrolase (sEH), drive damaging inflammation after injury. These metabolites, known as lipid mediators, regulate inflammation, blood pressure and pain. Drugs that inhibit the sEH enzyme and reduce inflammation could lead to better outcomes.

“Our previous work identified that these same lipid mediators were up-regulated in severe COVID infections, and we are now finding that these compounds play a role in modulating the immune response so that the body is unable to fight infection or respond properly to trauma without leading to a potentially fatal overreaction,” said Dr McReynolds.

“This dysregulation has fatal consequences in serious diseases such as COVID, cancer, sepsis, burn, where fatality rates can be as high as 40 percent in severe cases,” she said. “An understanding of these pathways can help identify patients at risk of developing serious disease or identify new therapeutic targets for treatment.”

“The immunological disbalance we see in many cases of severe burn injury, trauma and sepsis pose a huge clinical challenge as we lack the understanding of how to diagnose and treat it,” explained co-lead author Dr Christian Bergmann. “With this work, we reveal an important mechanism how immune cells are functionally disabled by sEH-derived metabolites of linoleic acid.”

“The natural compounds we are studying in this paper are metabolites of linoleic acid (LA), an essential fatty acid the body needs in very small amounts to survive and is only available through the diet,” Dr McReynolds elaborated. “At lower concentrations, these metabolites are necessary for regulating thermogenesis and heart health but promote inflammation at higher concentrations. LA is more stable and much cheaper than longer chain polyunsaturated fatty acids, so heavily processed foods have higher LA content to increase shelf-life. Additionally, agricultural practices, such as feeding animals corn-based diets, have increased LA in meats and dairy products.”

“As a result, we are consuming the highest amount of linoleic acid and have the highest recorded concentration of LA in our fatty tissue in human history,” McReynolds said. “As our bodies respond to stress or disease, we metabolise LA into the regulatory metabolites that were monitored in this paper. At higher concentrations, the immune system was unable to properly respond to infection, thereby promoting a sustained immune response. These observations are important in inflammatory-driven diseases, such as sepsis and COVID, but could also be important in understanding many of the increased chronic diseases we are seeing in our population.”

Source: UC Davis

Categories : Diet and NutritionTags :

Intermittent Fasting Triggers an Anti-inflammatory Response

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Credit: Intermountain Healthcare

Intermittent fasting may not only be a hot dieting trend, but it also has broader health benefits, including helping to fight inflammation, according to a new study. The new research shows that intermittent fasting raises the levels of galectin-3, a protein tied to inflammatory response.

Intermittent fasting has previously been shown to possibly improve health markers not related to weight. 

“Inflammation is associated with higher risk of developing multiple chronic diseases, including diabetes and heart disease. We’re encouraged to see evidence that intermittent fasting is prompting the body to fight inflammation and lowering those risks,” said Benjamin Horne, PhD, principal investigator of the study and director of cardiovascular and genetic epidemiology at the Intermountain Healthcare Heart Institute.

The findings of the study were presented at the American Heart Association’s Scientific Sessions 2021.

These results form part of Intermountain’s WONDERFUL Trial which is studying intermittent fasting. It found that intermittent fasting causes drops in metabolic syndrome score (MSS) and insulin resistance.  

This particular study followed 67 patients aged 21 to 70 who all had at least one metabolic syndrome feature or type 2 diabetes, and were also not taking anti-diabetic or statin medication, and had raised LDL cholesterol levels.

Of the 67 patients studied, 36 were prescribed an intermittent fasting schedule: twice a week water-only 24-hour fasting for four weeks, then once a week water-only 24 hour-fasting for 22 weeks. Fasts could not be done on consecutive days. The remaining 31 participants continued their routines.

After 26 weeks, participants’ galectin-3 was measured, and found to be higher in the intermittent fasting group. Lower rates of HOMA-IR (insulin resistance) and MSS (metabolic syndrome) were found, which researchers believe may be similar to the reported effects of SGLT-2 inhibitors.

“In finding higher levels of galectin-3 in patients who fasted, these results provide an interesting mechanism potentially involved in helping reduce the risk of heart failure and diabetes,” said Dr Horne, who added that a few members of the trial team completed the same regime before the study started to make sure that it was doable and not overly onerous for participants.

“Unlike some IF diet plans that are incredibly restrictive and promise magic weight loss, this isn’t a drastic form of fasting. The best routine is one that patients can stick to over the long term, and this study shows that even occasional fasting can have positive health effects,” he added.

Source: EurekAlert!

Categories : Medical Research & TechnologyTags :

New Type of Skin Cell Reveals Secrets of Inflammation

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The surprise discovery of a new type of cell explains how distress to the skin early in life may prime a person for inflammatory skin disease later, according to a new study in Nature. This finding will likely lead to treatments for autoimmune disorders like scleroderma, and inform understanding of inflammatory disease.

“The results reinforce the idea that what you’re exposed to initially may have lasting ramifications,” said lead researcher Michael Rosenblum, MD, PhD. “It appears that early exposure to inflammation can, through these cells we discovered, imprint an ability for tissues to develop inflammatory disease later in life.”

The team came across this new type of cell while investigating the effects of certain actions known to evoke immune response in mice. One of these actions involved knocking out a group of skin cells that suppress the immune system. Without that regulation, said Dr Rosenblum, a unique cell was observed that seemed to act as a shelter for pathogenic immune cells not typically seen in skin tissues.

“We had to knock out one cell population to see that they were controlling the growth and capacity of these other, unknown cells,” he said, noting that the new cells only became apparent in the tissue exposed to inflammatory triggers. “What normally would be a deserted island on the skin was now inhabited by all these strangers,” he said.

The team dubbed these strangers ‘TIFFs’ (Th2-interacting fascial fibroblasts) after the Th2 immune cells that they help to house. The location of TIFFs in the skin suggests that they belong to a group of cells that make up the fibrous connective tissue that is fascia, said lead author Ian Boothby, a graduate student in Dr Rosenblum’s lab.

“Because most organs have fascia of some sort, what we’re learning about TIFFs in skin may well be widely applicable to the rest of the body, meaning that these cells may play a role in a huge number of inflammatory diseases,” he said.

Boothby and Dr Rosenblum when skin without regulatory cells receives inflammatory triggers, the TIFFs spread like wildfire and become a sort of holding pen for the Th2 immune cells. Later in life, when there is even a small insult to the skin, Dr Rosenblum said, the TIFFs open their floodgates, unleashing the Th2 cells.

It seems that, through these cells, early exposure to inflammalation can leave a life-long imprint.

“All you need to do is push the immune system just a little bit, with a wound or with stress, to unleash all the pathogenic cells living in these TIFFs and create an exaggerated inflammatory response,” he said.

The researchers hypothesise that the exaggerated response may manifest as the creation of fibroses in the fascia, the driving force behind inflammatory skin diseases such as scleroderma.

To confirm the presence of TIFFs in human skin, the team obtained samples from volunteers with eosinophilic fasciitis (EF), a rare inflammatory disorder in which eosinophils build up in the skin fascia, the fibrous tissue between the skin and the muscles below it.

Comparing the EF samples to those of healthy skin, the researchers found TIFFs in both, but looked completely different. In healthy skin, the fascia forms a thin, spidery network between fat cells, while in the EF skin sample, the cells had expanded to form thick bands of fibrous tissue.

Revealing the mysteries of inflammation
TIFFs appear to be present in every organ, said Dr Rosenblum, usually found in the fascia surrounding major organs and serve a role in maintaining structure. They’re also prone to interacting with immune cells. He postulates that TIFFs might have evolved as a sort of emergency brigade in case of injury, able to jump-start repair in the case of internal injury.

“In patients with scleroderma or other fibrosing diseases like EF, that repair program may be kind of co-opted, resulting in this chronic wound-healing response,” said Dr Rosenblum. “If we can understand the biology of these cells, we can come in with drugs that revert them back to what they’re supposed to be doing.”

Source: University of California San Francisco

Categories : Respiratory DiseasesTags :

Distinct Lower Airways Bacterial Profile inChildren with Cystic Fibrosis

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Phot by Ben Wicks on Unsplash

In children with cystic fibrosis (CF), their lower airways have a higher burden of infection, more inflammation and lower diversity of microorganisms, compared to children with other illnesses who also have lung issues, researchers have found. They noted a clear divergence in these bacterial communities in toddlers, before progressive lung disease manifests in CF patients. 

Their findings, published in the journal PLOS ONE, could help providers target specific pathogens earlier, treat them and potentially prevent more severe lung disease.

As lead author Jack O’Connor, at Ann & Robert H. Lurie Children’s Hospital of Chicago explained, “We compared lower airway samples from bronchoscopy in children with CF and disease controls across the age spectrum, and used genetic sequencing to identify microorganisms, finding that a few common cystic fibrosis pathogens begin to dominate at very early ages. Such a clear split from disease controls in this young age group has not been shown before. Our findings deepen our understanding of the disease trajectory in cystic fibrosis and could help improve outcomes through earlier intervention.”

Chronic airway infection and inflammation which leads to progressive, obstructive lung disease is the main cause of illness and death in people with cystic fibrosis.

Researchers tested lower airway samples from 191 patients (63 with cystic fibrosis) aged 0-21 years. The disease controls included patients with diverse conditions, such as cancer, immune deficiency and pneumonia. Using genetic sequencing, researchers were able to identify distinct pathogens that are more dominant at different ages in patients with cystic fibrosis.

“Establishing key age-related differences in lower airway bacterial communities and inflammation in patients with CF, especially during early childhood, may give us a window of opportunity for earlier and more precise treatment,” said senior author Theresa Laguna, MD, MSCS, Division Head of Pulmonary and Sleep Medicine at Lurie Children’s and Associate Professor of Pediatrics at Northwestern University Feinberg School of Medicine. “If we can prevent worse infections, we could improve the quality of life and potentially expand the life expectancy of patients with CF.”

Source: News-Medical.Net

Categories : GastrointestinalTags :

Gut Microbes and Antibiotics Impact Inflammatory Pain

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C difficile. Source: CDC

A study in rats showed that gut microbiomes and antibiotic use could modulate inflammatory pain.

Published in The Journal of Pain, the study examined the impact of antibiotics on the gut microbiome and how antibiotic use can alter inflammatory pain in subjects with or without access to exercise.

According to Glenn Stevenson, Ph.D., professor of psychology within the School of Social and Behavioral Sciences, this is the first publication to assess how antibiotic-induced changes to the gut microbiome impact inflammatory pain distal to the gut (in the limbs, for example).

The study determined the effects of vancomycin on inflammatory pain-stimulated and pain-depressed behaviours in rats, which was induced with formalin. Oral vancomycin administered in drinking water attenuated pain-stimulated behaviour, and prevented formalin pain-depressed wheel running. Faecal microbiota transplantation produced a non-significant trend toward reversal of vancomycin’s effect on pain-stimulated behaviour. Vancomycin depleted Firmicutes and Bacteroidetes gut populations while partially sparing Lactobacillus species and Clostridiales. The vancomycin treatment effect was associated with an altered profile in amino acid concentrations in the gut.

The results indicate that manipulation of the gut microbiome may be one method to attenuate inflammatory pain amplitude. Additionally, results indicated that the antibiotic-induced shift in gut amino acid concentrations may be a causal mechanism for this reduction in pain.

The research for this study took four years to complete, Prof Stevenson said, adding that the link between amino acids and pain reduction is “highly novel.”

Source: University of New England