Tag: corticosteroids

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How Glucocorticoids Reprogram Immune Cells to Slow them Down

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Scanning electron micrograph of a T cell lymphocyte. Credit: NIH / NIAID

Cortisone and other related glucocorticoids are extremely effective at curbing excessive immune reactions. But previously, astonishingly little was known about how they exactly do that. A team of researchers have now explored the molecular mechanism of action in greater detail. As the researchers report in the journal Nature, glucocorticoids reprogram the metabolism of immune cells, activating the body’s natural “brakes” on inflammation. These findings lay the groundwork for development of anti-inflammatory agents with fewer and less severe side effects.

The glucocorticoid cortisone is naturally present in the body as the stress hormone cortisol, which is released to improve the body’s responses to stress. Cortisol intervenes in sugar and fat metabolism and affects other parameters, including blood pressure and respiratory and heart rate. At higher doses, it also inhibits immune system activity, making it it useful for medical purposes. Due to their excellent efficacy, synthetic glucocorticoid derivates that inhibit inflammation even more strongly are used to treat a wide range of immune-mediated inflammatory diseases.

Glucocorticoids affect not only genes, but also cellular energy sources

Glucocorticoid-based medications come with side effects, especially at higher doses and when administered for longer periods. These side effects are related to the other effects of the body’s own cortisol, and include hypertension, osteoporosis, diabetes, and weight gain. With the aim of developing anti-inflammatory agents with fewer and less severe side effects, a team of researchers from from Charité – Universitätsmedizin Berlin, Uniklinikum Erlangen and Ulm University has now conducted a closer study of how the immunosuppressive effects of glucocorticoids exactly works.

Lead researcher Prof Gerhard Krönke, director of the Department of Rheumatology and Clinical Immunology at Charité, explains: “It was previously known that glucocorticoids activate a number of genes in different cells of the body. But through this mechanism, they mainly activate the resources present in the body. This does not adequately explains its strong immunosuppressive effect. In our study, we have now been able to show that glucocorticoids affect more than just the gene expression in immune cells. It also affects the cell´s powerhouses, the mitochondria. And that this effect on cell metabolism is in turn crucial to the anti-inflammatory effects exerted by glucocorticoids.”

Swords to plowshares

For the study, the research team focused on macrophages, a type of immune cell responsible for eliminating intruders such as viruses and bacteria. These cells can also play a role in the emergence of immune-mediated inflammatory diseases. In a mouse model, the researchers studied how these immune cells responded to inflammatory stimuli in a laboratory setting and what effects additional administration of a glucocorticoid had. The researchers observed that in addition to its effect on gene expression, glucocorticoids had a major effect in reversing changes in the cell metabolism that had been initiated by the inflammatory stimuli.

“When macrophages are put into ‘fight’ mode, they redirect their cellular energy into arming for a fight. Instead of supplying energy, their mitochondria produce the components needed to fight intruders,” Krönke says, describing the processes involved. “Glucocorticoids reverse the process, switching the ‘fight’ mode back off and turning swords into plowshares, so to speak. A tiny molecule called itaconate plays an especially important role in this.”

Itaconate mediates anti-inflammatory effect of glucocorticoids

Itaconate is an anti-inflammatory substance that the body naturally produces inside its mitochondria. Macrophages produce it early on when they are activated so that the inflammatory reaction will subside after a certain period. Generation of this natural immune “brake,” however, requires sufficient fuel. When the cell´s powerhouses are arming up for a fight, that is no longer the case, so itaconate production dwindles to a halt after a while. With normal, short-term inflammation, this timing is effective because the immune response has also subsided in the meantime.

“With a persistent inflammatory stimulus, the drop-off in itaconate production is an issue because there is then no immune ‘brake’ even though the immune system is still running on all cylinders, eventually contributing to chronic inflammation,” explains Dr Jean-Philippe Auger, a scientist at the Department of Medicine 3 – Rheumatology and Immunology at Uniklinikum Erlangen and the first author of the study. “This is where glucocorticoids intervenes. By reprogramming the mitochondrial function, they ramp up the formation of itaconate in the macrophages, restoring its anti-inflammatory effect.”

The search for new active substances

Using animal models for asthma and rheumatoid arthritis, the researchers showed how much the anti-inflammatory effect of glucocorticoids depends on itaconate. Glucocorticoids had no effect in animals unable to produce itaconate. So, if itaconate mediates the immunosuppressant effect of cortisone, what about administering itaconate directly, instead of glucocorticoids?

“Unfortunately, itaconate isn’t a particularly good candidate as an anti-inflammatory drug, because it’s unstable, and due to its high reactivity, it could cause side effects if administered systemically,” Krönke explains. “Aside from that, we assume the processes in humans to be a bit more complex than those in mice. So our plan is to look for new synthetic compounds that are just as effective as glucocorticoids at reprogramming the mitochondrial metabolism inside immune cells, but have fewer and less severe side effects.”

Source: Charité – Universitätsmedizin Berlin

Categories : Ageing Skeletal SystemTags : Leave a comment

Intermittent Corticosteroid Use is Less Likely to Need Fracture Prevention Care

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Photo by Mehmet Turgut Kirkgoz on Unsplash

Prolonged use of corticosteroids, such as prednisolone, has been shown to cause osteoporosis increase fracture risk. The damage can increase the more corticosteroids are taken. But an analysis of prescribing data showed that for those taking intermittent doses of corticosteroids, there was less fracture risk.

Fracture preventive measures are recommended in cases of prolonged corticosteroid use, especially in older age. These can include referrals to specialist osteoporosis clinics or prescribing bisphosphonates.

In a study published in JAMA Dermatology, a team of researchers analysed data to determine whether corticosteroid prescription patterns may affect the likelihood that fracture prevention is considered. The authors, including researchers from the London School of Hygiene & Tropical Medicine (LSHTM), looked at data from across the UK and Ontario, Canada.

Dr Julian Matthewman, lead study author and Research Fellow at LSHTM, said, “Despite well understood benefits of fracture preventive care, including the use of bisphosphonates, previous research suggests that it is under-prescribed. One reason for this could be that doctors are not made aware when some patients have been prescribed an amount of corticosteroids that can damage the bones, such as when they are prescribed gradually or intermittently over multiple prescriptions, potentially even by several doctors.

“In our study, we focused on people aged 66 or older that were prescribed corticosteroids at a level where fracture preventive care should be considered. We used data from GP practices and hospitals across the UK and Ontario, Canada, including information on both corticosteroid and bisphosphonate prescriptions.

“We found that patients prescribed gradual or intermittent corticosteroids were indeed less likely to receive fracture preventive care as compared to patients prescribed corticosteroids in fewer but higher doses or longer-lasting prescriptions. In the UK, the former were about half as likely to receive fracture preventive care. In Ontario, they are about one third less likely.

“Fractures in older age can be dangerous, even deadly, cause disability and incur high costs for health care systems. Hip fractures alone cost the UK around £2 billion, and account for 1.8 million days spent in hospitals each year, according to the Office of Health Improvement & Disparities. Better recognizing patients who can benefit from proactive care has the potential to prevent fractures and their consequences.”

Source: London School of Hygiene & Tropical Medicine

Categories : Immune System NeurologyTags : Leave a comment

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 : Respiratory DiseasesTags : Leave a comment

Mepolizumab Weans Severe Asthma Patients off Steroids

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Asthma inhaler
Source: PIxabay/CC0

In a real world study, patients taking oral corticosteroids for severe asthma, taking mepolizumab reduced the need for those steroids by 75%. These findings were presented at the annual meeting of the American Academy of Allergy, Asthma & Immunology.

By the end study, patients on a median 10 mg maintenance dose of oral corticosteroids at baseline reduced their intake to 2.5 mg, reported Mark Liu, MD, of Johns Hopkins Medicine, who presented the findings.

And those on a median 5 mg maintenance dose at the start of the trial reduced their use to 0.4 mg by study end, Dr Liu said.

In the high steroid dose group, 36% were able to be weaned off the drugs by the end of the study, he reported. In the lower dose group, 49% were able to discontinue steroid use.

Treatment with the interleukin-5 (IL-5) antagonist mepolizumab reduced clinically significant annual exacerbations from a mean of 4.3 in the 12 months prior to the trial to 1.5 with mepolizumab use. This reduction from baseline was seen across all patient groups, said Dr Liu, including those with high and low steroid use and those who were not taking steroids at baseline to control symptoms.

Dr Liu suggested that despite the limitation of being a single-arm study, the “clinically important real-world findings indicate that patients with severe asthma treated with mepolizumab can reduce their oral corticosteroid use, potentially reducing the risk of side effects associated with their use, while improving their asthma control.”

The co-moderator of the presentation session, William Anderson, MD, of Children’s Hospital Colorado, said the study was important – “especially for our adult patients who are on chronic steroids, because the side effects of chronic steroids are so profound and oftentimes can lead to equal if not worse effects than the underlying asthma itself.”

“The ability to use a biologic agent to decrease the dose of an oral steroid for our patients is certainly extraordinarily promising,” Dr Anderson said to MedPage Today. “Our ultimate goal is to get patients off oral steroids.”

For the year-long study, Dr Liu and colleagues enrolled 822 adults with asthma and a new prescription for mepolizumab with at least 12 months of previous medical records. Mepolizumab was given at the standard 100mg subcutaneous dose.

“Patients with severe asthma often rely on oral corticosteroids to control their symptoms despite a well-recognized risk of complications even at low daily doses,” Dr Liu explained. The goal of the study, he said, was to determine what happened in a real-world setting when these patients were treated with mepolizumab, stratified by steroid use. The researchers enrolled patients from December 2016 through October 2019.

About 10% of patients experienced adverse events, but serious adverse events occurred in less than 1%, Dr Liu noted.

Source: MedPage Today