Researchers discover a critical cellular “off” switch for the inflammatory immune response that causes asthma attacks
Working with human immune cells in the laboratory, Johns Hopkins researchers report they have identified a critical cellular “off” switch for the inflammatory immune response that contributes to lung-constricting asthma attacks. The switch, they say, is composed of regulatory proteins that control an immune signaling pathway in cells.
“Asthma patients are constantly firing through this pathway because those proteins are stuck in the ‘on’ position, without proper control by other proteins that shut down this reaction,” says Nicola Heller, Ph.D., assistant professor of anesthesiology and critical care medicine at the Johns Hopkins University School of Medicine.
Asthma has been correlated with an overabundance of one type of immune cell called M2 macrophages in the lungs. In a nonasthmatic person, the M2 macrophages activate to clean up inhaled allergens and foreign particles, and then deactivate when the irritant is broken down.
However, in people with asthma, the M2 cells and the chemical signals they emit linger and call in other cells that cause inflammation that can trigger an asthma attack with the classic symptoms of difficulty breathing, wheezing and shortness of breath. Over time, the lung is changed by secretions from the M2 cells, which cause the lung tissue to remodel itself, contributing to irreversible obstruction and poor lung function. “If you prevent these cells from becoming the M2 type, you can potentially stop the continued inflammation and long-term structural changes,” says Heller.
The new research, reported Nov. 25 in the Journal of Biological Chemistry, investigated the role of two proteins, GRB10 and p70S6K, in the control of the signaling pathway that activates M2 cells.
In their previous work, also published in the Journal of Biological Chemistry Sept. 23, Heller’s group found that the inflammatory pathway involving the two proteins begins with interleukin 4 (IL-4), an immune system chemical that passes through a protein named IRS-2 before activating the M2 cells. They found that other proteins that stop the action of IRS-2 were not present in human M2 cells from people with allergies compared to healthy people. This made IRS-2 more active and increased the formation of M2 cells in people with allergies.
In the new study, Heller’s lab delved deeper into the IRS-2 pathway. By analyzing chemical changes of the IRS-2 protein in immortalized cultures of human white blood cells, it determined that IRS-2 appeared in two different forms — “on,” which allows the signal to pass through, and “off,” which stops the signal from activating the cells into M2 macrophages. They began by observing which proteins became active in the presence of IL-4 in human white blood cells and add “stop” signals to IRS-2. The activity of two regulatory proteins, GRB10 and p70S6K, increased after IL-4 exposure compared to the same cells that were not exposed to IL-4.
In further test tube experiments, the researchers treated the immortalized white blood cells with both chemical and genetic blockers, called small interfering RNA (siRNA), designed to render either p70S6K or GRB10 nonfunctional. The researchers saw that decreased GRB10 and p70S6K activity resulted in more of the “on” form of IRS-2, meaning these proteins are responsible for turning off IRS-2 and thereby downstream M2 production.
“This confirmed for us that without properly functioning GRB10 and p70S6K, the cells could not turn off IRS-2 signaling and M2 production,” says Heller.
The research team, Heller says, has already begun experiments to further explore the implications of these results, which include looking at differences in this pathway between cells taken from allergic and healthy individuals, and testing the efficacy of an inhalable drug that mimics the function of GRB1 and p70S6K to shut off the development of M2 macrophages in the lungs of mice. “One of the advantages of working with lung macrophages is that they are one of the first cells that see anything that gets put in an inhaler,” says Heller. “So we hope to modulate their activity in this way.”
These findings also have implications for treatment of cancer and other disorders, such as obesity, in which M2 macrophage cells play a regulatory role in tumor growth and fat deposition.
Learn more: Turning off Asthma Attacks
University of Leicester researcher in potential medical breakthrough
“This new drug could be a game changer for future treatment of asthma” – Professor Chris Brightling, NIHR Senior Research Fellow at the University of Leicester
The first new asthma pill for nearly 20 years has the power to significantly reduce the severity of the condition, a study led by the University of Leicester has found.
The research was funded by Novartis Pharmaceuticals, National Institute for Health Research (NIHR) and the EU (AirPROM), and is described by the lead researcher as “a game changer for future treatment of asthma.”
Three people die every day because of asthma attacks and research shows that two thirds of asthma deaths are preventable, according to Asthma UK.
Fevipiprant (QAW039) significantly decreased the symptoms of asthma, improved lung function, reduced inflammation and repaired the lining of airways.
The drug is currently being evaluated in late stage clinical trials for efficacy in patients with severe asthma, according to ClinTrials.gov.
A total of 61 people took part in the research. One group was given 225mg of the drug twice a day for 12 weeks and the other participants were assigned to a placebo group. Fevipiprant and the placebo were added to the medications the participants were already taking.
The study was designed primarily to examine the effects on inflammation in the airway by measuring the sputum eosinophil count.
The sputum eosinophil is an inflammation measurement of a white blood cell that increases in asthma and is used to assess the severity of this condition.
People who do not have asthma have a percentage of less than one and those with moderate-to-severe asthma typically have a reading of about five per cent.
The rate in people with moderate-to-severe asthma taking the medication was reduced from an average of 5.4 percent to 1.1 percent over 12 weeks, according to the study published today in the prestigious The Lancet Respiratory Medicine journal.
Professor Christopher Brightling, who is a NIHR Senior Research Fellow and Clinical Professor in Respiratory Medicine at the University of Leicester, led the study at the NIHR Respiratory Biomedical Research Unit, which is based at the Glenfield Hospital in Leicester.
Professor Brightling said: “A unique feature of this study was how it included measurements of symptoms, lung function using breathing tests, sampling of the airway wall and CT scans of the chest to give a complete picture of how the new drug works.
“Most treatments might improve some of these features of disease, but with Fevipiprant improvements were seen with all of the types of tests.
“We already know that using treatments to target eosinophilic airway inflammation can substantially reduce asthma attacks.
“This new treatment, Fevipiprant, could likewise help to stop preventable asthma attacks, reduce hospital admissions and improve day-to-day symptoms- making it a ‘game changer’ for future treatment.”
Gaye Stokes from Grantham in Lincolnshire has had severe asthma for 16 years. She took part in the trial and was part of the Fevipiprant group.
The 54-year-old said: “I knew straight away that I had been given the drug. I felt like a completely different person. I had more get up and go, I was less wheezy and for the first time in years I felt really, really well.
“For me, it felt like a complete wonder drug and I can’t wait for it to be available because I really think it could make a huge difference to me.”
After the 12 week trial and Gaye stopped receiving the drug, she said her health started to “go downhill again very quickly”.
Professor Brightling added that the latest advance underpinned the work of the Leicester Precision Medicine Institute, a Centre of Excellence that coalesces and aligns the research missions of the University of Leicester and the NHS in Leicester.
Future treatment of human disease will increasingly move from a ‘one size fits all’ approach to one of tailoring the treatment to the individual patient.
Asthma is a long-term condition that affects the airways. When a person with asthma comes into contact with something that irritates their sensitive airways it causes the body to react in several ways which can include wheezing, coughing and can make breathing more difficult.
The NIHR Leicester Respiratory Biomedical Research Unit – a partnership between the University of Leicester and Leicester’s Hospitals – focuses on promoting the development of new and effective therapies for the treatment of respiratory diseases including severe asthma and chronic obstructive pulmonary disease (COPD).