Neutrophil-derived extracellular vesicles promote feed-forward inflammasome signaling in cystic fibrosis airways.

Abstract

Cystic fibrosis (CF) airways feature high extracellular levels of the IL-1 family of proinflammatory mediators. These mediators are cleavage products of caspase-1, the final protease in the inflammasome cascade. Due to the proven chronic presence of reprogrammed neutrophils in the CF airway lumen, understanding inflammasome signaling in these cells is of great importance to understand how disease is perpetuated in this milieu. Here, we hypothesized that CF airway neutrophils contribute to chronic inflammation, in part, via the packaging of inflammasome-inducing signals in extracellular vesicles (EVs). We confirmed that CF airway fluid is enriched in IL-1α, IL-1β, and IL-18, and that CF airway neutrophils up-regulate the activating receptor IL-1R1. Meanwhile, down-modulatory signals such as IL-1R2 and IL-1RA are unchanged. Active caspase-1 itself is present in CF airway fluid EVs, with neutrophil-derived EVs being most enriched. Using a transmigration model of CF airway inflammation, we show that CF airway fluid EVs are necessary and sufficient to induce primary granule exocytosis by naïve neutrophils (hallmark of reprogramming) and concomitantly activate caspase-1 and IL-1β production by these cells and that the addition of triple-combination highly effective CFTR modulator therapy does not abrogate these effects. Finally, EVs from activated neutrophils can deliver active caspase-1 to primary tracheal epithelial cells and induce their 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 (naïve neutrophils and epithelial cells) via the transfer of bioactive EVs.

• Authors: Osric A Forrest, Brian Dobosh, Sarah A Ingersoll, Sanjana Rao, Alexander Rojas, Julie Laval, Jessica A Alvarez, Milton R Brown, Vin Tangpricha, Rabindra Tirouvanziam
• Journal: Journal of leukocyte biology (J Leukoc Biol) Vol. 112 Issue 4 Pg. 707-716 (10 2022) ISSN: 1938-3673 [Electronic] England
• PMID: 35172381 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: ©2022 Society for Leukocyte Biology.

Chemical References

• Inflammasomes
• Interleukin 1 Receptor Antagonist Protein
• Interleukin-18
• Receptors, Interleukin-1 Type II
• Cystic Fibrosis Transmembrane Conductance Regulator
• Peptide Hydrolases
• Caspases

Topics

• Caspases
• Cystic Fibrosis
• Cystic Fibrosis Transmembrane Conductance Regulator
• Extracellular Vesicles
• Humans
• Inflammasomes
• Inflammation
• Interleukin 1 Receptor Antagonist Protein
• Interleukin-18
• Neutrophils
• Peptide Hydrolases
• Receptors, Interleukin-1 Type II