Cellular switch to turn 'off' asthma attacks identified

Scientists have identified a critical cellular "off" switch for the inflammatory immune response that contributes to asthma attacks.
The switch, they say, is composed of regulatory proteins that control an immune signalling 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," said Nicola Heller, assistant professor 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 non-asthmatic 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 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, leading 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," said Heller.
Researchers studied the role of two proteins, GRB10 and p70S6K, in the control of the signalling pathway that activates M2 cells.

In their previous work, researchers 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, researchers delved deeper into the IRS-2 pathway.
By analysing chemical changes of the IRS-2 protein in 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.
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 tumour growth and fat deposition.