Estrogen synthesis, a process naturally occurring in the brains of zebra finches, may also fight off neuroinflammation caused by infection that occurs elsewhere in the body, new research indicates.
The IL-1 beta inhibitor canakinumab lowers the risk of cardiovascular disease and lung cancer risk by reducing inflammation.
Hemorrhagic fevers are severe viral diseases that are often fatal. Researchers have now identified messenger substances of the immune system, which in infected mice lead to the development of shock.
Researchers have repurposed an existing medication with healing properties traced to ancient Greeks.
Chemical compounds called cannabinoids are found in marijuana and also are produced naturally in the body from omega-3 fatty acids. A well-known cannabinoid in marijuana, tetrahydrocannabinol, is responsible for some of its euphoric effects, but it also has anti-inflammatory benefits. A new study in animal tissue reveals the cascade of chemical reactions that convert omega-3 fatty acids into cannabinoids that have anti-inflammatory benefits – but without the psychotropic high.
An enzyme present in the cornea that becomes dramatically upregulated and triggers inflammation during and even after a herpes virus infection has cleared has now been identified by researchers.
High doses of vitamin D taken one hour after sunburn significantly reduce skin redness, swelling, and inflammation, according to double-blinded, placebo-controlled clinical trial out of Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center. The trial results were recently published in the Journal of Investigative Dermatology.
In the study, 20 participants were randomized to receive a placebo pill or 50,000, 100,000, or 200,000 IU of vitamin D one hour after a small UV lamp “sunburn” on their inner arm. Researchers followed up with the participants 24, 48, 72 hours and 1 week after the experiment and collected skin biopsies for further testing. Participants who consumed the highest doses of vitamin D had long-lasting benefits — including less skin inflammation 48 hours after the burn. Participants with the highest blood levels of vitamin D also had less skin redness and a jump in gene activity related to skin barrier repair.
“We found benefits from vitamin D were dose-dependent,” said Kurt Lu, MD, senior author on the study and Assistant Professor of Dermatology at Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center. “We hypothesize that vitamin D helps promote protective barriers in the skin by rapidly reducing inflammation. What we did not expect was that at a certain dose, vitamin D not only was capable of suppressing inflammation, it was also activating skin repair genes.”
The trial is the first to describe acute anti-inflammatory benefits from taking vitamin D. According to the authors, despite widespread attention given to vitamin D deficiency, “there is a lack of evidence demonstrating that intervention with vitamin D is capable of resolving acute inflammation.” By measuring gene activity in the biopsies, the researchers also uncovered a potential mechanism behind how vitamin D aids skin repair. The results suggest vitamin D increases skin levels of an anti-inflammatory enzyme, arginase-1. The enzyme enhances tissue repair after damage and helps activate other anti-inflammatory proteins.
The study may have people flocking to vitamin supplement aisles, but Lu stresses that the trial tested very high doses of vitamin D that far exceed daily allowances. The Food and Drug Administration’s recommended adult daily allowance for vitamin D is 400 IU. Said Lu, “I would not recommend at this moment that people start taking vitamin D after sunburn based on this study alone. But, the results are promising and worthy of further study.” Lu and colleagues are planning additional studies that could inform treatment plans for burn patients.
Materials provided by Case Western Reserve University. Note: Content may be edited for style and length.
Immune cells in the brain trigger overeating and weight gain in response to diets rich in fat, according to a new study in mice led by researchers from UC San Francisco and the University of Washington Medical Center, and published online on July 5 in Cell Metabolism.
Neurons within a region at the base of the brain known as the hypothalamus, which plays a crucial role in eating, have long been a target for the development of drugs to treat obesity. But the new study suggests that brain-resident immune cells called microglia could also be targets for obesity treatments that might avoid many side effects of the obesity drugs currently in clinical use.
“Microglia are not neurons, but they account for 10 to 15 percent of the cells in the brain,” said Suneil Koliwad, MD, PhD, assistant professor of medicine at the UCSF Diabetes Center, and a co-senior author of the new study. “They represent an untapped and completely novel way to target the brain in order to potentially mitigate obesity and its health consequences.”
Microglia in the Hypothalamus are Responsible for Diet-Driven Weight Gain
A brain region called the mediobasal hypothalamus (MBH) contains key groups of neurons that regulate food intake and energy expenditure. Normally this region attempts to match the number of calories ingested in food with our need for energy to maintain a healthy weight, but previous research has shown that dietary fats can drastically throw off this balancing act.
In the new study, the researchers fed mice a fast food-like diet rich in fat for four weeks, which is known to cause microglia to expand in number and to trigger local inflammation within the MBH. Mice fed such a diet also eat more food, burn fewer calories, and gain more weight compared to mice eating a more healthy, low-fat diet.
To learn whether the multiplying microglia are a cause of overeating and obesity in these mice, rather than a result of their weight gain, Koliwad’s team at UCSF depleted the number of microglia in the MBH of mice on the fatty diet by giving them an experimental drug, called PLX5622, which is made by Plexxikon Inc., a Berkeley, California-based biotech company. The researchers found that mice treated with the drug ate 15 percent less and gained 20 percent less weight than untreated mice on the same diet.*
The University of Washington team, led by Joshua Thaler, MD, PhD, associate professor of medicine with the UW Medicine Diabetes Institute, genetically engineered mice to prevent microglia from activating inflammatory responses, and found that these mice ate 15 percent less and gained 40 percent less weight on a high fat diet, suggesting that the inflammatory capacity of microglia itself is responsible for the animals’ overeating and weight gain.
To confirm this finding, the UCSF researchers developed a strain of genetically engineered mice in which they could use a drug to activate the inflammatory response of microglia at will. They found that even in mice fed a healthy, low-fat diet, forcing microglia-induced inflammation in the hypothalamus caused mice to eat 33 percent more food and expend 12 percent less energy, leading to a four-fold (400 percent) increase in weight gain compared to untreated mice on the same healthy diet.
“From these experiments we can confidently say that the inflammatory activation of microglia is not only necessary for high-fat diets to induce obesity, but also sufficient on its own to drive the hypothalamus to alter its regulation of energy balance, leading to excess weight gain,” said Thaler, who was a co-senior author on the new paper.
Drugs Targeting Brain Inflammation Could Help Treat Obesity
It may soon be possible to learn whether eliminating microglia can thwart weight gain in humans as well. For example, another drug made by Plexxikon, called PLX3977, which is currently in clinical trials for hard-to-treat leukemias, solid tumors, and rare forms of arthritis, acts by the same biological mechanism as PLX522, the experimental drug the UCSF team used to reduce microglia numbers in the new study. It may thus be possible to see whether cancer patients in the PLX3977 trials experience beneficial effects on body weight, Koliwad said.
In their new paper, the researchers also report that high-fat diets trigger microglia to actively recruit additional immune-system cells from the bloodstream to infiltrate the MBH. Once there, the new recruits shape-shift to take on features similar to those of the brain’s own microglia, augmenting the inflammatory response and its impact on energy balance. Therefore, the authors said, it may be possible to control overeating and weight gain through multiple immunologic approaches — targeting bona fide microglia as well as targeting cells in the blood with the capacity to enter the hypothalamus and take on microglia-like functions.
The researchers next plan to further investigate how, exactly, consumption of high-fat foods leads to the activation of microglia, and whether there are ways to intervene to block these signals.
Did Microglia Evolve Ability to Help Animals Take Advantage of Rare Feasts?
Human brain imaging studies in recent years have found that, compared to lean individuals, those who are obese are more likely to have expanded populations of glial cells — the broader class of brain cells to which microglia belong — in the hypothalamus. This same sort of phenomenon, called gliosis, is commonly seen in neurodegenerative diseases, brain trauma, bleeding, infection and brain cancer, Koliwad said, leading researchers to initially conclude that dietary excess might essentially cause a form of brain injury.
But Koliwad believes that there could be a more positive explanation for the fact that microglia have evolved the ability to rapidly trigger increased appetite and weight gain in response to a high-fat diet: rich food was only rarely available during mammalian evolutionary history, and when it was available, it would be advantageous for animals to stop hunting or foraging and focus on chowing down.
“Microglial responsiveness to dietary fats makes some sense from this evolutionary perspective,” Koliwad said. “Fats are the densest form of calories that ancient humans might ever had the opportunity to consume. So, when primitive humans finally obtained a meal after a long period of fasting, microglia may have been essential in relaying the presence of this meal to those neurons that would stimulate maximal appetite.”
But in modern environments, in which high-fat food is continually available, this same adaptation can be damaging, Koliwad said. “In our modern world, when people constantly overeat rich, high-fat foods, chronic microglial activation could produce a more permanent stimulation of neural circuits that further increase high-fat food intake, leading to the development of a vicious cycle.”
Even in healthy individuals, the skin plays host to a menagerie of bacteria, fungi and viruses. Growing scientific evidence suggests that this lively community, collectively known as the skin microbiome, serves an important role in healing, allergies, inflammatory responses and protection from infection.
In a new study, researchers at the University of Pennsylvania have shown for the first time that, not only can infection with the Leishmania parasite alter the skin microbiome of affected mice, but this altered microbial community can be passed to uninfected mice that share a cage with the infected animals.
Mice with the perturbed microbiome, or dysbiosis, had heightened inflammatory responses and more severe disease when they were subsequently infected with Leishmania. The findings are published in the journal Cell Host & Microbe.
“To my knowledge, this is the first case where anyone has shown that a pre-existing skin microbiome can influence the outcome of an infection or a disease,” said Elizabeth Grice, co-senior author and assistant professor in the departments of Dermatology and Microbiology in Penn’s Perelman School of Medicine. “This opens the door to many other avenues of research.”
In addition, when the researchers examined samples from human Leishmania patients, they found similar patterns of dysbiosis as in the infected mice, a hint that the findings may extend to people.
“The transmission of dysbiosis in the skin from one animal to another is a key finding,” said Phillip Scott, professor of immunology in the Department of Pathobiology in Penn’s School of Veterinary Medicine and co-senior author on the study. “And the fact that we saw similar patterns of dysbiosis in humans suggests there could be some very practical implications of our work when it comes to treating people with leishmaniasis.”
Grice and Scott collaborated with researchers from Penn Medicine and Penn Vet, including lead author Ciara Gimblet, a Ph.D. student in Scott’s lab, and colleagues from Brazil’s Oswaldo Cruz Foundation.
Cutaneous leishmaniasis is a tropical disease caused by a parasite and transmitted by the bite of a sand fly. The disease results in sores on the skin, which can sometimes become severe and disfiguring. There is no vaccine for the disease and the limited drugs available often fail to provide a complete cure.
Curious about the influence of the skin microbiome on the disease, the Penn-led team swabbed the skin of 44 Leishmania patients, analyzing the microbiota not only of their lesions but also the area around them and a portion of skin on the opposite side of the bodies as the lesion. They noticed that the lesion samples contained less bacterial diversity than the samples of other skin sites. But not all of them were the same; they found three distinct community types: one dominated by Staphylococcus, one by Streptococcus and one that was mixed.
To get a clearer picture of how these microbiome shifts were connected to the disease, the researchers turned to a mouse model of Leishmania infection. Mirroring the findings in humans, the team found that infection with the Leishmania parasite induced a change in the skin microbiota in mice. They also found an association between the microbiota community type and disease severity. In mice that eventually resolved their infections, Staphylococcus dominated in the lesions, while Streptococcus was the dominant species in lesions on mice with a persistent, severe form of the disease.
A major discovery was that these shifts in microbiota were transmissible not only to other parts of the same mouse but to cage mates. When they kept mice infected with Leishmania in the same cage as uninfected mice for six weeks, the uninfected mice acquired a perturbed skin microbiome “profile” that resembled the infected mice.
The researchers hope to see whether the sharing of perturbed microbiota happens not just in mouse cages but also in households.
“I think an important next step will be to see if this sharing of microbiota occurs in people, and whether that could be a factor in affecting the severity of infections in humans,” Grice said.
A final question was to determine whether this naturally transmitted dysbiosis would predispose the uninfected animals’ response to an enhanced inflammatory response. And indeed, when infected with Leishmania, these mice had more severe inflammation and skin ulcers than mice with unperturbed skin microbiota. In a more general assay, the researchers used a contact hypersensitivity assay, which uses a skin irritant to elicit an immune response, on the mice that had been housed with Leishmania-infected mice. These dysbiotic mice, too, had a heightened inflammatory response.
To follow up on their findings, the researchers hope to examine whether sharing of a dysbiosis occurs in other infections and whether the resulting alteration in skin microbiota affect processes such as wound healing.
In addition, the Penn researchers will be working with their colleagues in Brazil to further examine the connections between the microbiome and leishmaniasis. Specifically, they hope to determine whether there is a connection between the type of skin microbiome present in Leishmania lesions and the severity of disease, or the responsiveness to treatment.
If true, “this may make us rethink the role of antibiotics in treating leishmaniasis,” Scott said.
Though previous studies are mixed about the effectiveness of antibiotics in alleviating the disease, additional information about the microbes that exacerbate inflammation could lead to more tailored therapies to tame skin lesions.