Breaking News
February 23, 2019 - AHA News: Why Are Black Women at Higher Risk of Dying From Pregnancy Complications?
February 23, 2019 - NIMH » Anxiety Disorders
February 23, 2019 - Autistic people urgently need access to tailored mental health support
February 23, 2019 - Newly designed molecule could benefit people with Friedrich’s Ataxia
February 23, 2019 - Chinese CRISPR twins may have better cognition and memory
February 23, 2019 - Study finds new genetic clues associated with asthma in African ancestry populations
February 23, 2019 - Fetal signaling pathways may offer future opportunities to treat lung damage
February 23, 2019 - Early-stage osteoarthritis drug wins prestigious innovation award
February 23, 2019 - Researchers report positive findings with dasotraline for ADHD in children ages 6-12
February 23, 2019 - News study reanalyzes the effects of noncaloric sweeteners on gut microbiota
February 23, 2019 - New device allows scientists to reproduce blow effects on the heart in lab
February 23, 2019 - Holy herb identified as a potential treatment for Alzheimer’s disease
February 23, 2019 - New technology platform digitally counts growth factors in single cells
February 23, 2019 - Surgery and other treatments offer viable options for adult scoliosis
February 23, 2019 - Reduced antibody adaptability may make the elderly more vulnerable to influenza
February 23, 2019 - Neighborhood income, education associated with risk of disability progression in MS patients
February 23, 2019 - 2019 guidelines for management of patients with atrial fibrillation
February 23, 2019 - Surprise rheumatoid arthritis discovery points to new treatment for joint inflammation
February 23, 2019 - A just-right fix for a tiny heart
February 23, 2019 - UMass Amherst scientist explores role of citrus peel in decreasing gut inflammation
February 23, 2019 - Owlstone Medical and Shanghai Renji Hospital collaborate to initiate breath biopsy lung cancer trial
February 23, 2019 - AMSBIO’s comprehensive portfolio of knock-out cell lines and lysates
February 23, 2019 - New app reliably determines physicians’ skills in forming accurate, efficient diagnoses
February 23, 2019 - Peripheral nerve injury can trigger the onset and spread of ALS, shows study
February 23, 2019 - Researchers uncover mechanisms that prevent tooth replacement in mice
February 23, 2019 - Once-a-day capsule offers new way to reduce symptoms of chronic breathlessness
February 23, 2019 - FDA Adds Boxed Warning for Increased Risk of Death with Gout Medicine Uloric (febuxostat)
February 23, 2019 - Phone-based intervention aids rheumatoid arthritis care
February 23, 2019 - Opioid epidemic makes eastern inroads and targets African-Americans
February 23, 2019 - New identified biomarker predicts patients who might benefit from HER2-targeted agents
February 23, 2019 - Study offers new insights into mechanisms of changes in erythrocytes under stress
February 23, 2019 - Antipsychotic polypharmacy may be beneficial for schizophrenia patients
February 23, 2019 - Researchers investigate how marijuana and tobacco co-use affects quit attempts by smokers
February 23, 2019 - Patients with diabetes mellitus have high risk of stable ischemic heart disease
February 23, 2019 - Transparency on healthcare prices played key role in Arizona health system’s turnaround
February 23, 2019 - A comprehensive, multinational review of peppers around the world
February 23, 2019 - Study finds modest decrease in burnout among physicians
February 23, 2019 - A simple change can drastically reduce unnecessary tests for urinary tract infections
February 23, 2019 - Deep Learning-Enhanced Device Detects Diabetic Retinopathy
February 23, 2019 - Researchers discover new binding partner for amyloid precursor protein
February 23, 2019 - Modest decrease seen in burnout among physicians, researchers say | News Center
February 23, 2019 - Transplanting bone marrow of young mice into old mice prevents cognitive decline
February 23, 2019 - Mogrify to accelerate novel IP and cell therapies using $3.7m USD funding
February 23, 2019 - Johns Hopkins study describes cells that may help speed bone repair
February 23, 2019 - Scientists demonstrate influence of food odors on proteostasis
February 23, 2019 - Researchers unlock the secret behind reproduction of fish called ‘Mary’
February 23, 2019 - Acupuncture Could Help Ease Menopausal Symptoms
February 23, 2019 - Researchers use AI to detect early signs of Alzheimer’s
February 23, 2019 - On recovery, vulnerability and ritual: An exhibit in white | News Center
February 23, 2019 - Memory Stored in Unexpected Region of the Brain
February 23, 2019 - Several health experts worldwide gather at EUDONORGAN event
February 23, 2019 - Discovery of potent compound in native California shrub may lead to treatment for Alzheimer’s
February 22, 2019 - Researchers create new map of the brain’s own immune system
February 22, 2019 - ICHE’s reviews on surgical infections, unnecessary urine tests, and nurses’ role in antibiotic stewardship
February 22, 2019 - UK Research and Innovation invests £200 million to create new generation of AI leaders
February 22, 2019 - Takeda collaboration to boost fight against Alzheimer’s and other neurodegenerative diseases
February 22, 2019 - Heavy drinking may change DNA, leading to increased craving for alcohol
February 22, 2019 - U.S. opioid deaths jump fourfold in 20 years; epidemic shifts to Eastern states | News Center
February 22, 2019 - 5 Questions with William Turner on Diversity in Medicine
February 22, 2019 - HHS Finalizes Rule Seeking To Expel Planned Parenthood From Family Planning Program
February 22, 2019 - Researchers uncover biochemical pathway that may help identify drugs to treat Alzheimer’s
February 22, 2019 - Biologist uses new grant to find ways to eliminate schistosomiasis
February 22, 2019 - Bag-mask ventilation to help patients breathe during intubation prevents complications
February 22, 2019 - AbbVie Announces New Drug Application Accepted for Priority Review by FDA for Upadacitinib for Treatment of Moderate to Severe Rheumatoid Arthritis
February 22, 2019 - Nature versus nurture and addiction
February 22, 2019 - New website connects researchers with data experts, resources | News Center
February 22, 2019 - Today’s Concerns About Drug Prices Echo The Past
February 22, 2019 - CT and Doppler equipment have low accuracy in detecting cerebral vasospasm and ischemia
February 22, 2019 - Study finds out similarity in function between healthy retina cell and tumor cell
February 22, 2019 - CWRU awarded NIH grant to identify effective treatments for intimate partner violence
February 22, 2019 - Oncotype DX Not Cost-Effective for Low-Risk Breast Cancer
February 22, 2019 - Scientists discover new type of immune cells that are essential for forming heart valves
February 22, 2019 - Talk About Déjà Vu: Senators Set To Re-Enact Drug Price Hearing Of 60 Years Ago
February 22, 2019 - Genetic defect linked to pediatric liver disease identified
February 22, 2019 - New cellular atlas could provide a deeper insight into blinding diseases
February 22, 2019 - Growing number of cancer survivors, fewer providers point to challenge in meeting care needs
February 22, 2019 - Innovative compound offers a new therapeutic approach to treat multiple sclerosis
February 22, 2019 - $1.5 million grant to develop opioid treatment program for jail detainees
February 22, 2019 - FDA’s new proposed rule would update regulatory requirements for sunscreen products in the U.S
February 22, 2019 - Most Hip, Knee Replacements Last Decades, Study Finds
Location matters for inflammation clearance

Location matters for inflammation clearance

image_pdfDownload PDFimage_print

Where a protein is expressed can influence its action. University of Pennsylvania researchers and colleagues have identified one that plays a key role in getting the body back to normal after inflammation.

Health conditions that involve inflammation run the gamut, from multiple sclerosis and lupus to arthritis, diabetes, and cancer. While inflammation can serve as a normal response to help the body deal with injury or infection, problems arise when it persists, potentially harming surrounding tissues.

To prevent or ameliorate this damage, the body relies on a strategy to actively clear inflammation. “It’s not just extinguishing the fire of inflammation,” says George Hajishengallis of the University of Pennsylvania. “You also have to return things to the way they were before the inflammatory destruction.”

A new study led by Hajishengallis, the Thomas W. Evans Centennial Professor in Penn’s School of Dental Medicine, and Triantafyllos Chavakis of the Technical University of Dresden has illuminated a key player in this resolution process, the protein Del-1, which the pair has studied extensively before. While prior research had underscored Del-1’s role in curbing the initiation of inflammation, the new work finds that it can serve a very different function, actively working to clear inflammation. Which function the protein performs depends on the cell type that expresses it, the team found.

“Our findings prompted us to propose the ‘location principle’ in the spatial regulation of the immune response,” says Chavakis. “In other words, homeostatic molecules–those responsible for maintaining equilibrium in the body–may perform different regulatory functions depending on their location.”

The work appears in the journal Nature Immunology.

Hajishengallis, Chavakis, and their labs and collaborators have been interested in the protein Del-1 for many years. Through a series of experiments and publications, they’ve established its importance in the initiation of inflammation. Focusing on periodontitis, severe gum disease, as a model system, they’ve found Del-1 restrains the activity of neutrophils, preventing damaging inflammation and bone loss in the gums.

In the new work, they wanted to see whether Del-1 could also act not just to hold back inflammation from occurring in the first place but also to actively resolve it once it occurred.

In collaboration with co-author Jonathan M. Korostoff, professor of periodontics at Penn Dental Medicine, they found that, in humans with periodontitis, Del-1 levels rose upon treating the disease. To follow up on the finding and get at a mechanism, they turned to a mouse model of gum disease, observing that Del-1 expression levels rose when the animals’ disease began to resolve, a mirror to the human data.

“Just because Del-1 goes up doesn’t necessarily mean anything,” says Hajishengallis, “but, when we did the same experiment with mice that lack Del-1, the resolution of inflammation failed.”

That suggested to the scientists that Del-1 was a necessary component of the resolution process. To further explore this possibility, they turned to another disease, peritonitis, which involves inflammation of the abdominal lining.

Here they saw the same effect and were further able to show a course of action: Del-1 was able to act as a molecular bridge to expedite the clearance of dying neutrophils by connecting them to macrophages, a distinct type of immune cells that engulf and “eat” cellular debris, and thus maintaining a healthier environment. This process of clearing dying neutrophils is called efferocytosis.

Importantly, Del-1 appeared to reprogram the efferocytic macrophages toward a type that contributes to resolution and tissue repair. Mice lacking a domain of Del-1 that interacts with macrophages were not able to promote efferocytosis.

In addition to promoting this clearance of neutrophils, the researchers discovered that Del-1 also induced a group of molecular mediators called resolvins, which promote inflammation resolution. The researchers hypothesize that Del-1 may regulate a positive feedback loop, in which it triggers resolvins and then acts downstream of them to get things back in order after inflammation clears.

Perhaps the most novel finding of the paper, was what the researchers have termed the “location principle.” In their earlier studies, they had found Del-1 secreted from endothelial cells that line tissues was responsible for regulating initiation of inflammation by inhibiting the traffic of neutrophils. But other work has shown that macrophages, too, could secrete Del-1. Using mice that overexpressed either the endothelial-derived Del-1 or the macrophage-derived Del-1, they found that the cell type mattered when it came to the protein’s activity. Overexpressing Del-1 only in endothelial cells, for example, made no difference in the animals’ ability to clear dying neutrophils in a model of peritonitis. Conversely, mice overexpressing Del-1 in their macrophages had no advantage in harnessing neutrophil recruitment but were better able to clear the neutrophils from the site of inflammation.

“This ‘location principle’ is novel,” says Hajishengallis. “Tissues are not a sack of molecules; the geography is very important.

“As a pro-resolution protein, Del-1 is probably acting downstream of therapeutics that promote periodontal health,” he adds. “For instance, the complement inhibitor AMY-101, which can cause a rise in Del-1 levels, may depend on Del-1 to accelerate the resolution of inflammation.”

“This fundamental mechanism of inflammation clearance by Del-1,” says Chavakis, “may also be involved in multiple inflammatory pathologies, including metabolic-inflammatory or malignant disease.”

Source:

https://penntoday.upenn.edu/news/resolve-inflammation-location-matters

Tagged with:

About author

Related Articles