Stress-fighting proteins give new hope for asthma cure

New research from Weill Cornell Medical College may give hope to the 1 in 12 Americans affected by asthma.

In a study published July 6 in Nature Immunology, investigators detail their discovery of the precise molecular steps enabling immune cells found in certain forms of asthma and other allergies to both develop and survive in the body.

The discovery opens the door to a possible new pathway for the development of more effective treatments and therapies for asthma.

In the past, researchers found that an oversupply of immune cells that help defend the body against parasites and infection, called eosinophils, participate in inflammatory processes such as asthma and other allergic diseases. Not much was known about how eosinophils develop and survive.

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(Image credit to Sarah Bettigole and Raphael Lis)

Lead study author Sarah Bettigole, a postdoctoral fellow at Weill Cornell, and colleagues found that a signaling pathway, formed by two proteins that help cells survive stressful conditions, is also key in eosinophil development. When her team disrupted the function of either of those proteins, the eosinophils, but not other cell types, underwent excess stress and die off, implying that this pathway may serve as a new therapeutic target for patients whose disease responds poorly to current asthma therapies.

According to the National Institute of Allergy and Infectious Diseases, eosinophils belong to a group of cells called granulocytes, which develop in the bone marrow before migrating into blood.

During early stages of development, these cells produce a large number of proteins that are essential for survival, as well as toxic proteins that are released later in response to an immune trigger, such as bacteria or viruses. Intense bursts of protein production during normal biological processes put pressure on the endoplasmic reticulum (ER).

"The ER is a key cellular organelle responsible for folding and processing of secreted and transmembrane proteins," explains lead study author Sarah Bettigole, a postdoctoral fellow at Weill Cornell. "If incorrectly folded proteins accumulate beyond a safe level, cells enter a state of 'ER stress,' which can be corrected by several ER stress response proteins."

Eosinophils are responsible for several debilitating disorders including hypereosinophilic syndromes, Churg-Strauss syndrome, eosinophilic leukemia, eosinophilic esophagitis, and certain subtypes of asthma, Bettigole tells Medical Economics.

Her group found that an ER stress response protein known as XBP1 is critical for the development of an immune cell known as an eosinophil, which is linked to asthma and a variety of other illnesses. When XBP1 or a separate enzyme known as IRE1, which activates XBP1, were genetically deleted in mice, all eosinophil development ceased.

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"We believe that the ER within developing eosinophils undergoes massive strain while producing high quantities of secretory granule proteins," Bettigole says. "Without XBP1 to compensate for this strain, eosinophil transcriptional identity is suppressed as an adaptation, which is ultimately unsustainable and leads to cell death.

"Though several specific anti-eosinophil pharmaceuticals have been recently developed, patients do not respond equally to clinical intervention, indicating the need for alternative therapeutic strategies," she says. "There is currently significant interest in developing small molecule inhibitors of IRE1 for diseases such as cancer and systemic lupus erythematosus. This study now shows that small molecule inhibitors to IRE1, which are currently of significant interest to the pharmaceutical industry, could be repurposed to treat eosinophil-dependent diseases."

The study is the first to show that eosinophil development can be potently and specifically blocked by interfering with the function of a single enzyme, IRE1.

"This enzyme is pharmacologically tractable, and therefore is be a viable therapeutic target for developing new anti-eosinophil drugs," Bettigole says.