Abstract
Fungal infections represent a worldwide health problem. Fungal pathogens are responsible for a variety of conditions, including superficial diseases, allergic pathologies and potentially lethal invasive infections. Neutrophils and eosinophils have been implicated as effector cells in several pathologies. Neutrophils are major effector cells involved in the control of fungal infections and exhibit a plethora of antifungal mechanisms, such as phagocytosis, reactive oxygen species production, degranulation, extracellular vesicle formation, and DNA extracellular trap (ET) release. Eosinophils are polymorphonuclear cells classically implicated as effector cells in the pathogenesis of allergic diseases and helminthic infections, although their roles as immunomodulatory players in both innate and adaptive immunity are currently recognized. Eosinophils are also endowed with antifungal activities and are abundantly found in allergic conditions associated with fungal colonization and sensitization. Neutrophils and eosinophils have been demonstrated to release their nuclear and mitochondrial DNA in response to many pathogens and pro-inflammatory stimuli. ETs have been implicated in the killing and control of many pathogens, as well as in promoting inflammation and tissue damage. The formation of ETs by neutrophils and eosinophils has been described in response to pathogenic fungi. Here, we provide an overview of the mechanisms involved in the release of neutrophil and eosinophil ETs in response to fungal pathogens. General implications for understanding the formation of ETs and the roles of ETs in fungal infections are discussed.
Highlights
INTRODUCTIONNeutrophils and eosinophils have been implicated as effector cells in infections caused by fungal pathogens and in diseases associated with allergic sensitization to fungi (Yoon et al, 2008; Lilly et al, 2014; Gazendam et al, 2016a; Figueiredo and Neves, 2018)
A few years later, a subsequent study showed that the stimulation of human eosinophils with thymic stromal lymphopoietin (TSLP), a cytokine secreted by epithelial cells and known to contribute to the promotion of Th2 responses, induced the release of extracellular trap (EET) of mitochondrial origin in a mechanism independent of cell death but dependent on the activation of NADPH oxidase and a β2-integrin (Morshed et al, 2012)
The process of EET release involving cell death was described, introducing the concept of EETosis, where eosinophils undergo a cytolytic process with nuclear disruption, DNA mixing with intact granules and release of chromatin and associated granules into the extracellular medium in an NADPH oxidasedependent mechanism (Ueki et al, 2013)
Summary
Neutrophils and eosinophils have been implicated as effector cells in infections caused by fungal pathogens and in diseases associated with allergic sensitization to fungi (Yoon et al, 2008; Lilly et al, 2014; Gazendam et al, 2016a; Figueiredo and Neves, 2018). ABPMs have a profile of a Th2 inflammatory response with eosinophilic infiltrates, the nature of the interactions between eosinophils and fungi is unclear, and the participation of eosinophils in fungal infections continues to be extensively discussed, as eosinophils played no role in certain aspects of the pulmonary pathology in the experimental ABPM induced by Aspergillus fumigatus exposure (Dietschmann et al, 2020) Whether these findings are relevant clinically or are limited to the experimental model utilized remains to be elucidated. We review the mechanisms by which ETs are released from neutrophils and eosinophils in response to fungal pathogens and the role of these ETs in pathologies caused by fungal infections or hypersensitivity responses to fungi and their antigens
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