Evidence of eosinophil extracellular trap cell death in COPD: does it represent the trigger that switches on the disease?

Abstract

In spite of the numerous studies on chronic obstructive pulmonary disease (COPD), the cellular and molecular basis of the disease’s development remain unclear. Neutrophils and eosinophils are known to be key players in COPD. Recently, neutrophil extracellular trap cell death (NETosis), a mechanism due to decondensation and extrusion of chromatin to form extracellular traps, has been demonstrated in COPD. However, there is limited knowledge about eosinophil extracellular trap cell death (EETosis) and its role in the pathogenesis of COPD. The aim of this study was to evaluate EETosis in stable COPD. Induced sputum obtained from healthy smokers and low exacerbation risk COPD A or B group patients or high exacerbation risk COPD C or D group patients were included. Samples were examined using electron microscopy and immunofluorescence. Healthy smokers (n=10) and COPD A (n=19) group exhibited neutrophilic or paucigranulocytic phenotypes, with NETosis being absent in these patients. In contrast, COPD B (n=29), with eosinophilic or mixed phenotypes, showed EETosis and incipient NETosis. COPD C (n=18) and COPD D groups (n=13) were differentiated from low exacerbation rate-COPD group by the abundant cellular debris, with COPD C group having an eosinophilic pattern and numerous cells undergoing EETosis. A hallmark of this group was the abundant released membranes that often appeared phagocytosed by neutrophils, which coincidentally exhibited early NETosis changes. The COPD D group included patients with a neutrophilic or mixed pattern, with abundant neutrophil extracellular trap-derived material. This study is the first to demonstrate EETosis at different stages of stable COPD. The results suggest a role for eosinophils in COPD pathophysiology, especially at the beginning and during the persistence of the disease, regardless of whether the patient quit smoking, with EETosis debris probably triggering uncontrolled NETosis. The main target of these findings should be young smokers with the potential to develop COPD.

Eosinophil Extracellular Traps and Inflammatory Pathologies—Untangling the Web!

“…The concomitant presence of EETs and NETs in COPD sputum was reported recently ( 25 ). The authors concluded that EETs may contribute to the severity of COPD.…”

“…Similar extracellular traps (ETs) have subsequently been observed from other cells of the innate family members, for example, mast cells ( 22 ), monocytes ( 23 ), tissue macrophages ( 24 ), and eosinophils ( 18 , 25 – 27 ). Recently, even lymphocytes, key effector cells of the adaptive immune system, were demonstrated to eject ETs in vitro when incubated with serum obtained from systemic erythematous lupus (SLE) patients ( 28 ).…”

“…EETosis was demonstrated in vivo in induced sputum plugs from COPD (chronic obstructive pulmonary disease) patients. Increased eosinophil free granules and cellular debris were found associated with EETs, and MBP was shown to co-localize with observed DNA-based ETs ( 25 ). Again, immobilized IgG (50 μg/mL) and immunoprecipitated immunoglobulins from the sputum of severe eosinophilic asthmatics with increased anti-EPX IgG titers were shown to trigger extensive EETs in vitro from isolated peripheral eosinophils within 3–12 h of incubation ( 36 ).…”

Characterization and implications of the dynamics of eosinophils in blood and in the infarcted myocardium after coronary reperfusion

“…Similar to neutrophils, eosinophils also display potent pro-coagulative and disruptive functions. In fact, eosinophil extracellular traps have been evidenced not only in coronary thrombi but also in a variety of inflammatory pathologies [ 25 ]. The presence of eosinophils in zones with MVO in experiments parallels the more severe eosinopenia detected in STEMI patients with MVO.…”

β2-Adrenoceptors inhibit neutrophil extracellular traps in human polymorphonuclear leukocytes

“…NET primarily identified, produced by neutrophils to kill microorganisms and to defend against pathogens, are demonstrated to be formed also during inflammatory events, as for example, in cystic fibrosis, thrombosis, and chronic obstructive pulmonary disease . In the last years, the list of diseases in which these neutrophil products are demonstrated to be involved was certainly increased and a key role of NET in non‐infective diseases was recently outlined .…”