A Cleveland Clinic research team has discovered how a protein on the surface of immune system mast cells in the lungs facilitates the cells’ proliferation, contributing to severe inflammation and progression to asthma.
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Although more research is needed to fully understand mast cell hyperproliferation, inhibiting the surface protein known as MCEMP1 (mast cell-expressed membrane protein 1) could be a new approach to treating asthma and other inflammatory lung conditions.
The research took place in the lab of Jae Jung, PhD, Chair of Cleveland Clinic Lerner Research Institute’s Cancer Biology Department, Director of the Infection Biology program, and Director of the Sheikha Fatima bint Mubarak Global Center for Pathogen & Human Health Research.
“A rapid increase in mast cell numbers is associated with more severe cases of asthma,” says Youn Jung Choi, PhD, a postdoctoral fellow in Dr. Jung’s lab and the paper’s first author. “What we discovered is a new molecular mechanism that, if turned off, can reduce the number of mast cells and, therefore, the level of inflammation.”
Probing mast cell proliferation
Inflammation is part of the innate immune response. Severe asthma is caused by excessive airway inflammation in response to a trigger such as allergens or air pollution particulates. Inflammation causes airway swelling and narrowing, making breathing difficult. Asthma afflicts more than 25 million people in the U.S. and 300 million people worldwide.
Inhaled asthma therapeutics treat airway inflammation but do not address the underlying biological causes of its recurrence.
Mast cells reside in lung tissue. There, they play a key role in immune response and inflammation. Triggered by external signaling molecules that bind to surface receptors, mast cells release inflammation-inducing compounds, undergo growth and proliferation, and recruit additional immune cells, among other actions. Previous research has established that mast cells’ KIT receptors, activated by binding with stem cell factor (SCF), signal the cells to grow, survive and proliferate.
The degree to which mast cells accumulate in inflamed lung tissue correlates with asthma severity and progression. Likewise, the level of MCEMP1 expression in mast cells correlates with asthma severity, suggesting a critical role for this transmembrane protein in the disease process.
However, MCEMP1’s precise molecular mechanism has remained unknown, as has the means by which mast cells proliferate in the lungs of asthma patients and whether inhibiting mast cell proliferation would mitigate asthma progression and severity.
The researchers conducted a series of in vitro and in vivo experiments and analyses to investigate MCEMP1’s molecular functioning and the consequences of its activation. They used mouse and human mast cells and employed a mouse model of chronic asthma that they developed.
Among their findings:
- MCEMP1 interacts with and activates the KIT receptor’s signaling activity.
- MCEMP1 expression is important for SCF-induced proliferation of mast cells. Conversely, loss of MCEMP1 expression impairs SCF-induced mast cell proliferation.
- In the mouse model of chronic asthma, a deficiency of MCEMP1 reduces airway inflammation, alters gene expression related to lung inflammation and damage and eases lung function impairment.
Collectively, according to Dr. Choi and her colleagues, their results indicate that MCEMP1 helps mediate immune responses and promotes mast cell proliferation, which is a factor in severe asthmatic lung inflammation.
More work remains to be done to better understand MCEMP1’s role in other mast cell functions besides proliferation, and to fully grasp all signaling pathways and molecular mechanisms that determine mast cell hyperproliferation.
Inhibiting mast cell activation and reducing mast cell numbers are promising approaches to treat inflammatory, allergic lung cell diseases. Considering MCEMP1’s key roles in activation and proliferation, developing MCEMP1 inhibitors would seem to be a fruitful direction for future research, the researchers conclude.
While MCEMP1 is highly expressed in lung cells, its expression also is induced during immune responses in other parts of the body. That shows the value of searching for MCEMP1 functions beyond the lungs, Dr. Choi says.
“Understanding how this mechanism works in the lung not only provides us with a path to new therapies for asthma, but it could be a finding that helps us map out similar functions in other inflammatory diseases in the lung and throughout the body,” she says.