Eosinophils: Focus on DNA extracellular traps.

Eosinophils are multitasking granulocytes with implications for allergies, host response to helminths and, more recently, described roles in immunomodulation, homeostasis and tissue remodeling. Eosinophils secrete their preformed granule proteins by different pathways, especially piecemeal degranulation and cytolysis with granule release. Currently, there are different insights related to eosinophils' functional roles and biology that deserve to be highlighted. Cytolysis with granule release has also been associated with DNA extracellular trap formation, one of the most intriguing, recently described mechanisms of leukocyte activation. Focusing on DNA extracellular trap release, there are lessons to be learned from neutrophils considering the multitasking roles of these structures in inflammation, and the mechanisms involved in their release. This review explores a comparative analysis of the current knowledge considering DNA traps extrusion in neutrophils and eosinophils and update the major findings regarding the presence of these entities in eosinophilic-associated immune responses, inflammation and diseases.

Structural and Signaling Events Driving Aspergillus fumigatus-Induced Human Eosinophil Extracellular Trap Release.

Eosinophils are granulocytes classically involved in allergic diseases and in the host immune responses to helminths, fungi, bacteria and viruses. The release of extracellular DNA traps by leukocytes is an important mechanism of the innate immune response to pathogens in various infectious conditions, including fungal infections. Aspergillus fumigatus is an opportunistic fungus responsible for allergic bronchopulmonary aspergillosis (ABPA), a pulmonary disease marked by prominent eosinophilic inflammation. Previously, we demonstrated that isolated human eosinophils release extracellular DNA traps (eosinophil extracellular traps; EETs) when stimulated by A. fumigatus in vitro. This release occurs through a lytic non-oxidative mechanism that involves CD11b and Syk tyrosine kinase. In this work, we unraveled different intracellular mechanisms that drive the release of extracellular DNA traps by A. fumigatus-stimulated eosinophils. Ultrastructurally, we originally observed that A. fumigatus-stimulated eosinophils present typical signs of extracellular DNA trap cell death (ETosis) with the nuclei losing both their shape (delobulation) and the euchromatin/heterochromatin distinction, followed by rupture of the nuclear envelope and EETs release. We also found that by targeting class I PI3K, and more specifically PI3Kδ, the release of extracellular DNA traps induced by A. fumigatus is inhibited. We also demonstrated that A. fumigatus-induced EETs release depends on the Src family, Akt, calcium and p38 MAPK signaling pathways in a process in which fungal viability is dispensable. Interestingly, we showed that A. fumigatus-induced EETs release occurs in a mechanism independent of PAD4 histone citrullination. These findings may contribute to a better understanding of the mechanisms that underlie EETs release in response to A. fumigatus, which may lead to better knowledge of ABPA pathophysiology and treatment.