Scientists have found what may be a critical trigger in allergic asthma, estimated to affect 60% of the 28 million Americans with the chronic respiratory condition. The discovery opens the door to new ways to protect airways from the pathway that leads to inflammation and its symptoms.
Researchers from the Shanghai Institute of Biochemistry and Cell Biology and the Shanghai Institute of Materia Medica, both part of the Chinese Academy of Sciences (CAS), found that when common allergens such as pollen and dust mites come in contact with the lungs, they cause airway cells to release stored iron.
This "free iron" then activates a protein known as gasdermin D (GSDMD), which triggers the release of the immune signaling molecule interleukin 33 (IL-33).
IL-33 is released by epithelial cells to alert immune cells to the site of damage. In this case, the airways. Cell biopsies have previously shown that people with these chronic issues have much higher IL-33 activity levels than individuals without asthma.
Essentially, IL-33 initiates the chain reaction that leads to allergic inflammation, mucus production, and airway damage.
Using a mouse model, the scientists found that allergens activated a receptor on airway cells, triggering them to release stored iron. The iron interacted with GSDMDm, generating highly reactive molecules that activated the protein, in turn alerting IL-33 to a problem.
This iron-led process also bypasses the immune pathways that have long been thought to be responsible for the allergic reaction.
When the scientists suppressed the amount of available iron in cells, using an iron-binding drug, they were able to significantly reduce airway irritation and lower the levels of inflammatory immune cells and mucus.
Adding extra iron, however, had the opposite effect, ramping up inflammation and the physical symptoms of allergic asthma.
This opens the door to developing ways to either control the amount of iron available or block this newly identified iron-signaling pathway for treating allergic asthma and other allergic diseases.
"Blocking any step of this iron-GSDMD pathway, via iron chelation or genetic ablation, abolishes IL-33 secretion, prevents group 2 innate lymphoid cell (ILC2) activation, and mitigates allergic airway inflammation and tissue damage in mice," the team writes.
Of course, the clear limitation is that the research is in its early stages, with the pathway only identified in mice. So further studies will be needed to see if iron plays the same kind of role in the airways of humans with chronic allergic conditions.
"Our findings reveal an unconventional, iron-catalyzed, and protease-independent mechanism for GSDMD activation, offering potential new therapeutic targets for allergic inflammatory diseases," the researchers note.
The research was published in the journal Cell.
Source: Chinese Academy of Sciences via MedicalXpress
Fact-checked by Mike McRae
