The findings of a new study published in the Journal of Leukocyte Biology support the idea that extracellular vesicles are critical in the pathology of cystic fibrosis (CF) and other neutrophilic airway diseases.
According to the authors of the study, more research targeting the extracellular vesicles is needed to better understand the potential therapeutic benefit of this approach.
It is already known that reprogrammed neutrophils are constantly present in the airways of patients with CF. A better understanding of inflammasome signaling in these cells can shed light on how the disease continues in this environment.
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“Here, we hypothesized that CF airway neutrophils contribute to chronic inflammation, in part, via the packaging of inflammasome-inducing signals in extracellular vesicles,” the researchers wrote.
First, they confirmed that fluid from the airways of CF patients was enriched in interleukin (IL) 1α, IL-1β, and IL-18. Moreover, the neutrophils in CF airways upregulated the activating receptor IL-1 receptor type 1.
The researchers also demonstrated that active caspase-1, the final protease in the inflammasome cascade that gives rise to the IL-1 family of proinflammatory mediators, was present in the extracellular vesicles, especially those derived from neutrophils, in the airway fluid of patients with CF.
They showed that extracellular vesicles from the airways of CF patients are necessary and sufficient to induce primary granule exocytosis by naïve neutrophils, which is a hallmark of reprogramming, and the production of activated caspase-1 and IL-1β by these cells.
Finally, they showed that extracellular vesicles from activated neutrophils can deliver active caspase-1 to tracheal cells and induce the release of IL-1α.
“These findings support the existence of a feed-forward inflammatory process by which reprogrammed CF airway neutrophils bypass 2-step control of inflammasome activation in neighboring cells,” the researchers concluded.
Forrest OA, Dobosh B, Ingersoll SA, et al. Neutrophil-derived extracellular vesicles promote feed-forward inflammasome signaling in cystic fibrosis airways. J Leukoc Biol. Published online February 16, 2022. doi:10.1002/JLB.3AB0321-149R