Scientists Discover Stress-Fighting Pathway Could Help Develop New Asthma Treatments

Scientists Discover Stress-Fighting Pathway Could Help Develop New Asthma Treatments

In a recent study published in Nature Immunology, scientists from the Weill Cornell Medical College were able to identify the molecular steps that enable immune cells implicated in certain forms of asthma and allergy to develop and survive in the body. The study findings may have implications for lung conditions such as asthma.

Asthma causes the immune system to be overactive to normally harmless substances such as pollen or mold.

In previous studies, the researchers demonstrated that an overabundance of eosinophils, which as specific immune cells can protect the body against infection and parasites, may play a role in the cause of asthma.

To understand how eosinophils develop and survive, the team discovered that two proteins that form a signaling pathway, which helps immune cells to survive in stressful conditions, are also responsible for the development of eosinophils.

“Our findings demonstrate that individual cell types, particularly eosinophils, interpret and manage stress in distinct ways,” said lead author Dr. Sarah E. Bettigole, a postdoctoral fellow at Weill Cornell in a recent news release . “If we disrupt the ability to respond to stress, sensitive cells like eosinophils die off. These subtle differences could be leveraged to develop novel therapies for diseases like asthma and eosinophilic leukemia.”

Eosinophil granulocytes, usually called eosinophils or eosinophiles are white blood cells and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along with mast cells, they also control mechanisms associated with allergy and asthma. They are granulocytes that develop during hematopoiesis in the bone marrow before migrating into the blood.

During early stages of development, eosinophils produce proteins that are vital for survival, and they also produce toxic proteins that are released in response to an immune trigger, such as bacteria or viruses.

An overproduction of proteins during typical biological processes cause stress on the structure of a cell, known as endoplasmic reticulum. The endoplasmic reticulum is responsible for the synthesis and transport of proteins. If the ER is overwhelmed by such strain, the cell enters a state known as ER stress.

A protein called IRE1α was found to generate a highly active form of a second protein called XBP1, in response to ER stress. This second protein then was found to regulate various gene activity, which are involved in the cell stress response. The results from the study also showed that this signaling pathway is able to reduce ER stress and prevent the death of the cell by increasing the ER’s protein synthesis aptitude, at the same time as it reduces the production of the protein.

“Because XBP1 supports the survival of certain mature cell types that make a lot of protein throughout their lives, we suspected that XBP1 might also help cells like eosinophils cope with intense bursts of protein production during development,” said senior author Dr. Laurie H. Glimcher, the Stephen and Suzanne Weiss Dean of Weill Cornell Medical College, in a news release.

The team of researchers discovered that the IRE1α/XBP1 signaling pathway turned out to be very active in the differentiation of eosinophils. The researchers also found that eosinophils were also able to produce more proteins progressive developmental stages.

For the study, the researchers used genetically modified mice lacking XBP1 and found that these were also lacking eosinophils in the spleen bone marrow and blood, while other granulocytes were unaffected.

“So far, XBP1 is the only transcription factor to our knowledge that distinguishes the development of eosinophils from that of other granulocytes,” Dr. Glimcher said in the news release. “This suggests that subtle differences in cellular biological processes provide a previously unappreciated handle for fine-tuning the production of different types of granulocytes.”

The results from the study also showed that XBP1 loss in the eosinophils was responsible for the alteration of gene activity, which are essential for the ER stress response, which leads to substantial ER swelling, an accumulation of inadequately processed proteins, and severe dysfunction in the granule.

In the mice lacking XBP1, the research team found that eosinophils in development experienced too much stress, which delayed their ability to differentiate by blocking the GATA1 molecule. This molecule is responsible for ensuring the maturation of young eosinophils into adult eosinophils.

The scientists discovered that too much stress and too few GATA1 molecules were responsible for the death of the eosinophils.

Based on these results, the researchers suggested that ER health is vital for the development and survival of eosinophis. These results highlight the potential use of the IRE1α/XBP1 signaling pathway as therapeutic target for eosinophil-mediated conditions.

The team of researchers is now looking at the potential efficacy of experimental XBP1 or IRE1α inhibitors for the treatments of eosinophil leukemia and asthma.

“We now know that XBP1 is required for normal eosinophil development, but we need to figure out whether eosinophil-mediated respiratory illnesses and cancers are also dependent on this pathway,” Dr. Bettigole said in the news release. “If these diseases are eosinophil- dependent, blocking IRE1α or XBP1 with pharmaceuticals would be an exciting new treatment strategy.”


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