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The nervous system is known to communicate with the immune system and regulate inflammation in the body. Researchers at Karolinska Institutet in Sweden now show how the electrical activation of a specific nerve can promote healing in acute inflammation. The finding, which is published in the journal PNAS, opens new ways to accelerate the resolution of inflammation.
The way the body regulates inflammation is only partly understood. Previous research by Peder Olofsson’s group at Karolinska Institutet and other research groups has shown that electrical stimulation of the vagus nerve can reduce inflammation. Such nerve stimulation has been used with encouraging results in clinical studies of patients with inflammatory bowel disease and rheumatoid arthritis. However, how nerve signals regulate the active resolution of inflammation was unclear.
“We have now studied the effects of signals between nerves and immune cells at the molecular level,” says April S. Caravaca, a researcher in Peder Olofsson’s group at the Department of Medicine, Solna, Karolinska Institutet and the Stockholm Center for Bioelectronic Medicine at MedTechLabs. “A better understanding of these mechanisms will allow for more precise applications that harness the nervous system to regulate inflammation.”
The researchers showed that electrical stimulation of the vagus nerve in inflammation shifts the balance between inflammatory and specialised anti-inflammatory molecules, which promotes healing.
“Inflammation and its resolution play a key role in a wide range of common diseases, including autoimmune diseases and cardiovascular diseases,” says Peder Olofsson. “Our findings provide insights on how the nervous system can accelerate the resolution of inflammation by activating defined signalling pathways.”
The researchers will continue to study how nerves regulate the healing of inflammation in more detail.
“The vagus nerve is only one of many nerves that regulate the immune system. We will continue to map the networks of nerves that regulate inflammation at the molecular level and study how these signals are involved in disease development,” says Dr Olofsson. “We hope that this research will provide a better understanding of how pathological inflammation can resolve, and contribute to more effective treatments of the many inflammatory diseases, such as atherosclerosis and rheumatism.”
The SARS-CoV-2, or the novel coronavirus, has affected more than 500 million people worldwide. Apart from the symptoms associated with COVID-19 infection, it has recently been reported that the virus also leads to the subsequent development of autoimmune diseases in patients.
Autoimmune diseases like rheumatoid arthritis, lupus, or multi-inflammatory syndromes arise when the immune system confuses healthy cells with pathogens and starts attacking them. But, the precise mechanism underlying this “breach of self-tolerance” is unknown. One of the possible mechanisms suggested to be involved is what is called “molecular mimicry,”
in which an autoimmune reaction is triggered when a T-cell receptor or an antibody produced from a B-cell directed against a specific antigen (foreign body) binds with an autoantigen, which is an antigen produced from our own body. This occurs due to a molecular or structural resemblance between the “epitopes” (the part of antigen attached to the antibody) of the antigens. However, a comprehensive investigation of the role of molecular mimicry in the development of such autoimmune diseases has not yet been performed due to the complexity of the epitope search and the lack of standardized tools.
To this end, a team of researchers from the Gwangju Institute of Science and Technology (GIST) led by Prof. Jihwan Park developed a new bioinformatics pipeline. Their new tool, called cross-reactive-epitope-search-using-structural-properties-of-proteins (CRESSP), was recently reported in the journal Briefings in Bioinformatics. “Previous studies on molecular mimicry used bioinformatics pipelines different from one another that often involved complex algorithms and were not scalable to proteome scales. In light of this, we developed a pipeline that is easily accessible and scalable,” explains Prof. Park. “It uses the structural properties of proteins to identify epitope similarities between two proteins of interest, such as human and SARS-CoV-2 proteins.”
Using CRESSP, the team screened 4,911,245 proteins from 196,352 SARS-CoV-2 genomes obtained from an open-access database. The pipeline narrowed down 133 cross-reactive B-cell and 648 CD8+ T-cell epitopes that could be responsible for COVID-related autoimmune diseases. It further identified a protein target, PARP14, to be a potential initiator of epitope spreading between COVID-19 virus and human lung proteins.
The pipeline also predicted the cross-reactive epitopes of different coronavirus spike proteins. Moreover, the team developed an interactive web application to enable an interactive visualization of the molecular mimicry map of SARS-CoV-2. The pipeline is also available as an open-source package.
The team hopes their new tool will facilitate comparison between studies, providing a robust framework for further investigation on molecular mimicry and autoimmune diseases. “Although autoimmune diseases affect less than 10% of the population, studying them is important since it severely impacts the quality of life. Our new tool can be used to study the possible involvement of molecular mimicry in the development of other autoimmune conditions in a systemic and scalable manner,” concludes Prof Park.
Hopefully, the new invention will help us deal with SARS-CoV-2 and other viral infections better.
of the junction between the danger sensor NLRP3 and its signal protein, shown in magnification with the calculated protein structure. CREDITImage: Inga V. Hochheiser
Redness, swelling, pain – these are signs of inflammation. It serves to protect the body from pathogens or foreign substances. Researchers from the Universities of Bonn and Cologne were able to show that inflammatory reactions of an important sensor protein proceed in a specific spatial direction. This finding has the potential to conceivably stop inflammation at the “growing end”, and thus bring chronic inflammatory diseases to a halt. The study has now been published in the journal “Science Advances“.
If bacteria or viruses attack living cells or other foreign substances appear in them, the danger sensor with the abbreviation NLRP3 is activated. “The protein deposits in the brain that are characteristic of Alzheimer’s disease, the so-called amyloid-ß plaques, can also set NLRP3 in motion,” says Prof. Dr. Matthias Geyer from the Institute for Structural Biology at the University Hospital Bonn, referring to earlier studies. As these previous studies by the researcher’s show, this reaction increasingly fuels itself: The inflammatory reaction triggered by NLRP3 promotes the further deposition of amyloid-ß plaques and contributes significantly to the disease process.
Once activated, several NLRP3 proteins attach to each other and in this way form the nucleus for a thread-like structure at which more and more proteins gather. “The reaction kicks in as soon as about a dozen of the NLRP3 molecules are present,” Geyer reports. In theory, an infinite number of NLRP3 molecules can join together and extend the thread-like structure – scientifically called a “filament” – further and further. Inga Hochheiser from Prof. Geyer’s team has now been able to show the direction in which this filament grows and continues to expand. “We were able to gain these insights using cryo-electron microscopy. This method makes it possible to observe protein molecules with up to 80,000-fold magnification and thus make them directly visible,” says Hochheiser.
“Still image” of the thread-like structure under the microscope
In tiny steps, the scientist drizzled NLRP3 isolated from cells onto a sample carrier and flash-froze this mixture. This provided the researchers with a kind of “still image” under the cryo-electron microscope. The emerging thread-like structure of NLRP3 molecules arranged side by side was thus visualized. “These individual images made it possible to understand how the filaments elongate, just like in a film,” says Hochheiser. As the molecules fall differently on the sample carrier when drizzled, they can be seen from different perspectives under the microscope. These different views can be combined on the computer to create a three-dimensional image. The results showed that the filaments only form in one direction. “This allowed us to visualize part of the inflammatory apparatus and literally read the direction of growth,” says Prof. Geyer, who led the study and is a member of the Cluster of Excellence ImmunoSensation2 and the Transdisciplinary Research Area “Life and Health” at the University of Bonn.
Stopping chronic inflammatory diseases
“The technical challenge was to find the transitions in the thread-like structures and make them visible in the image,” says Prof. Dr. Elmar Behrmann from the Institute for Biochemistry at the University of Cologne. “The new findings now allow us to target the growing end of the inflammatory response using antibodies or drugs,” Hochheiser explains. This brings the researchers closer to their goal of stopping the further build-up of the inflammatory apparatus and thus counteracting chronic inflammation.
Inflammation in the gums can increase susceptibility to other forms of inflammation, such as arthritis, through changes to immune cell precursors in the bone marrow, according to new research led by Penn scientists and collaborators. CREDIT Katie Vicari
The immune system remembers. Often this memory, primed by past encounters with threats like bacteria or viruses, is an asset. But when that memory is sparked by internal drivers, like chronic inflammation, it can prove detrimental, perpetuating a misguided immune response.
In a new paper in Cell, researchers from the School of Dental Medicine, together with an international team including colleagues at the Technical University of Dresden, lay out the mechanism by which innate immune memory can cause one type of inflammatory condition—in this example, gum disease—to increase susceptibility to another—here, arthritis—through alterations to immune cell precursors in the bone marrow. In a mouse model, the team demonstrated that recipients of a bone marrow transplant were predisposed to more severe arthritis if their donor had inflammatory gum disease.
“Although we use periodontitis and arthritis as our model, our findings go above and beyond these examples,” says George Hajishengallis, a professor in Penn Dental Medicine and a corresponding author on the work. “This is in fact a central mechanism, a unifying principle underlying the association between a variety of comorbidities.”
The researchers note that this mechanism may also prompt a reconsideration of how bone marrow donors are selected, as donors with certain types of immune memory caused by underlying inflammatory conditions might put bone marrow transplant recipients at a higher risk of inflammatory disorders.
Basis in the bone marrow
In previous work, Hajishengallis had partnered with co-corresponding author Triantafyllos Chavakis of Technical University of Dresden and collaborators to explore the role of innate immune memory. Their findings showed that, just like the adaptive immune system’s T cells and B cells, the innate immune system’s myeloid cells, such as neutrophils and macrophages, could “remember” past encounters, becoming more responsive when exposed to a new threat. The work also pinpointed how this memory was encoded, tracing it to the bone marrow, and showed that this “trained immunity” could be transferred from one organism to another through a bone marrow transplant, protecting recipients from cancer through an innate immune response.
While that is good news, Hajishengallis and Chavakis also believed that trained immunity could be detrimental in the right contexts. While attending a meeting on innate immunity in Greece in 2019, the two scientists brainstormed over dinner at an outdoor tavern, jotting down their thoughts on a napkin. They later formalized some of their hypotheses about this potential “dark side” of trained immune in a publication in Nature Reviews Immunology in 2021.
“The thoughts went like this: We knew the gum disease periodontitis increased the risk of comorbidities like cardiovascular disease,” says Hajishengallis. “And the reverse is also true: People with the inflammatory disease colitis, for example, have an increased prevalence of periodontal disease. Different mechanisms have been proposed, but no one unifying mechanism could explain this bidirectionality.”
“We started thinking about a possible unifying mechanism that could underlie the association between several distinct comorbidities,” says Chavakis.
Building on their earlier discovery related to “trained” precursors in the bone marrow, the scientists set out to see whether they could trace the source of the association between comorbidities to the innate immune training they already knew was happening in the bone marrow.
Setting out to test this hypothesis, the team first showed that, within a week of inducing a mouse to have periodontal disease, the animal’s myeloid cells and their progenitor cells expanded in the bone marrow. Examining these cells weeks later, after periodontitis was intentionally resolved, the researchers did not notice significant changes in how the cells looked or behaved.
However, these progenitor cells appeared to have memorized the inflammation they were exposed to, as they harbored important epigenetic changes: alterations in molecular markers that affect the ways genes are turned on and off but do not alter the actual DNA sequence. The researchers found that these alterations, triggered by inflammation, could alter the manner in which the genes would be expressed after a future challenge. The overall pattern of epigenetic changes, the researchers noted, was associated with known signatures of the inflammatory response.
Mice with induced periodontal disease also had more severe responses to a later immune system challenge, evidence of trained immunity.
To put the whole picture together regarding the link between inflammatory conditions, the “critical experiment,” as Hajishengallis explains, was a bone marrow transplant. Mice that had periodontitis, a severe form of gum disease, served as donors, as did a group of healthy mice serving as controls. Two hundred stem cells from their bone marrow were transplanted into mice that had never had gum disease and which had had their own bone marrow irradiated. A few months later, these mice were exposed to collagen antibodies, which trigger arthritis.
“Mice that received the transplant from mice with periodontitis developed more severe arthritis than mice that received a donation of stem cells from periodontally healthy mice,” says Hajishengallis.
“And higher joint inflammation in recipient mice was due to inflammatory cells deriving from the periodontitis-trained stem cells,” says Chavakis.
Further experiments suggested that the signaling pathway governed by a receptor for the molecule IL-1 played a vital role in contributing to this inflammatory memory. Mice that lacked IL-1 receptor signaling could not generate the immune memory that made the recipient mice more susceptible to comorbidities, the researchers found.
The work has implications for bone marrow transplants in humans, a common course of therapy in addressing blood cancers.
“Of course, it’s a great thing if you find a matching donor for bone marrow transplantation,” says Hajishengallis. “But our findings suggest that it’s important for clinicians to keep in mind how the medical history of the donor is going to affect the health of the recipient.”
The work also underscores that blocking IL-1 receptor signaling could be an effective approach to mitigate against these knock-on effects of trained immunity.
“We’ve seen anti-IL-1 antibodies used in clinical trials for atherosclerosis with excellent results,” Hajishengallis says. “It could be that it was in part because it was blocking this maladaptive trained immunity.”
Follow-up projects are examining how other inflammatory conditions, may be linked with periodontal disease, a sign, the researchers say, of how crucial oral health is to overall health.
“I’m proud for the field of dentistry that this work, with significance to a wide range of medical conditions, began by investigating oral health,” Hajishengallis says.