Eosinophils: More Than Just Cell Death?
"Unpacking the Debate Around Eosinophil Cytolysis and Extracellular Trap Formation"
Eosinophils, a type of white blood cell, are key players in inflammatory conditions like asthma and nasal polyps. Recent research has focused on how these cells contribute to tissue inflammation, particularly through the formation of eosinophil extracellular traps (EETs).
A central question in this research area is whether eosinophil cell death (cytolysis) is necessary for EET formation. Persson and Ueki commented on a recent article, sparking a debate about this very topic. This article will further explore the nuances of eosinophil behavior, EET formation, and the role of cell death in these processes.
We aim to clarify the current understanding of eosinophil function, addressing whether cell death is a prerequisite for EET formation or if these are independent events. By unpacking this debate, we can better understand the complexities of eosinophil activity and its impact on inflammatory diseases.
Rapid DNA Release Beyond Cell Death
In a reported experiment, lipopolysaccharide from Gram-negative bacteria activated IL-5- or interferon-gamma-primed eosinophils to release mitochondrial DNA. The release depended on reactive oxygen species but occurred independently of eosinophil death. It happened in less than one second, in a catapult-like manner.
Limits of Current Assessment
Eosinophil cytology alone may not distinguish reactive from clonal eosinophilia: striking abnormalities can occur in reactive cases, while clonal cells may look fairly normal. For airway eosinophilia, sputum cytology using routine dithiothreitol (DTT) processing is well established, but its multistep protocol requires substantial resources and may limit wider clinical use. These examples show that accepted assessment methods can have interpretive or practical limitations.
Ehrlich’s 1879 Discovery
In 1879, Paul Ehrlich used acidic dyes to stain human peripheral blood smears and identified a leukocyte that strongly bound eosin. He named it an “eosinophil,” and his staining procedure is still used to examine peripheral blood. Eosinophilia became recognizable as a hematological phenomenon after nineteenth-century advances in microscopic blood analysis.
Eosinophil Cytolysis and EET Formation: Are They Linked?
The idea that inhibiting eosinophil apoptosis contributes to tissue eosinophilia is well-established. However, the relationship between eosinophil apoptosis, cytolysis, and EET formation is more complex.
- RIPK3-MLKL Pathway: Eosinophil cytolysis depends on the receptor-interacting protein kinase 3 (RIPK3)-mixed lineage kinase-like (MLKL) pathway.
- EET Formation: The formation of extracellular DNA traps can occur independently of the RIPK3-MLKL pathway.
- Independent Processes: This suggests that EET formation and eosinophil cytolysis are distinct phenomena.
EETosis Is Not a Settled Finding
A live-cell imaging study reported that human eosinophils did not form extracellular traps or undergo EETosis after stimulation with PMA, MSU crystals, or opsonized C. albicans. At the same time, there is currently no gold-standard method for identifying EETosis. A commonly described feature is active eosinophil lysis that releases cell-free granules and net-like chromatin, underscoring the need to interpret claims of trap formation with care.
Rethinking EETosis: The Future of Eosinophil Research
Given the complexities, the term "EETosis," implying that eosinophil death is required for EET formation, may be a misnomer. Lyzed granulocytes produce a DNA cloud, whereas EETs are defined by DNA fibers.
Context Shapes Eosinophil Research
A 2025 review explores eosinophil recruitment, immune interactions, therapeutic potential, and methods for studying eosinophils in the tumor microenvironment. It suggests that better understanding their role there may support new therapeutic strategies and position eosinophils as targets or biomarkers in precision oncology. Separately, observations in severe asthma suggest eosinophils may already be primed to undergo cytolysis before reaching the bronchial wall.
Balancing Homeostasis and Disease
Human data summarized in a 2021 review suggest eosinophils contribute to body homeostasis and defense against parasitic, bacterial, and viral infections, participate in cancer immunology, and also have pathological roles in eosinophilic diseases. Another review notes their involvement in allergic disease, including fibrotic responses in asthma. For hypereosinophilic syndrome (HES), early use of therapies that reduce eosinophil counts is usually effective in avoiding irreversible organ damage. The source also emphasizes identifying disease triggers and etiology, and recognizing distinct eosinophil subsets, to understand disease progression.
Clinical Associations and Cell Protection
A real-world study of patients with non-small cell lung cancer (NSCLC) receiving immune checkpoint inhibitors evaluated absolute eosinophil count (AEC) and eosinophil percentage (E%) in relation to treatment outcomes. Higher AEC and E% at cycle 4 were associated with improved overall survival, while E% at cycle 4 was significantly associated with longer progression-free survival; these are reported associations, not proof of causation. A separate study suggests that increased autophagy in eosinophils protects against cytolysis and DNA release, limiting the discharge of potentially damaging intracellular contents.
The coexistence of EETs and clusters of extracellular granules in tissues can be explained by sequential participation of the same eosinophil in EET formation and subsequent cytolysis. Therefore, understanding the distinct mechanisms and triggers for EET formation and eosinophil cytolysis is essential for developing targeted therapies.
Further research should focus on the specific signals that initiate each process and how these pathways can be modulated to reduce inflammation without compromising host defense mechanisms. A more nuanced understanding of eosinophil behavior will pave the way for more effective treatments for eosinophil-associated inflammatory diseases.