Increased Circulating Cell-Free DNA in Eosinophilic Granulomatosis With Polyangiitis: Implications for Eosinophil Extracellular Traps and Immunothrombosis

Hashimoto, Teppei; Ueki, Shigeharu; Kamide, Yosuke; Miyabe, Yui; Fukuchi, Mineyo; Yokoyama, Yuichi; Furukawa, T.; Azuma, Naoto; Oka, Nobuyuki; Takeuchi, Hiroki; Kanno, Kyoko; Ishida‐Yamamoto, Akemi; Taniguchi, Masami; Hashiramoto, Akira; Matsui, Kiyoshi

doi:10.3389/fimmu.2021.801897

Cited by 30 publications

(16 citation statements)

References 60 publications

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“…Eosinophils seem to react with excessive EET formation to sputum immunoglobulins and were also found in the sputum plugs of COPD patients ( 120 ), maybe indicating a preserved function of extracellular traps in mucosal immunity and/or parasite infections. In EGPA, EETs were detected in small-vessel thrombi, correlated with D-dimer levels and induced platelet adhesion, identifying EETs as the main miscreant in immunothrombosis in EGPA ( 121 ).…”

Section: The Pathophysiological Influence Of Platelet-net Interplay I...mentioning

confidence: 99%

Platelets in the NETworks interweaving inflammation and thrombosis

2022

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Platelets are well characterized for their indispensable role in primary hemostasis to control hemorrhage. Research over the past years has provided a substantial body of evidence demonstrating that platelets also participate in host innate immunity. The surface expression of pattern recognition receptors, such as TLR2 and TLR4, provides platelets with the ability to sense bacterial products in their environment. Platelet α-granules contain microbicidal proteins, chemokines and growth factors, which upon release may directly engage pathogens and/or contribute to inflammatory signaling. Additionally, platelet interactions with neutrophils enhance neutrophil activation and are often crucial to induce a sufficient immune response. In particular, platelets can activate neutrophils to form neutrophil extracellular traps (NETs). This specific neutrophil effector function is characterized by neutrophils expelling chromatin fibres decorated with histones and antimicrobial proteins into the extracellular space where they serve to trap and kill pathogens. Until now, the mechanisms and signaling pathways between platelets and neutrophils inducing NET formation are still not fully characterized. NETs were also detected in thrombotic lesions in several disease backgrounds, pointing towards a role as an interface between neutrophils, platelets and thrombosis, also known as immunothrombosis. The negatively charged DNA within NETs provides a procoagulant surface, and in particular NET-derived proteins may directly activate platelets. In light of the current COVID-19 pandemic, the topic of immunothrombosis has become more relevant than ever, as a majority of COVID-19 patients display thrombi in the lung capillaries and other vascular beds. Furthermore, NETs can be found in the lung and other tissues and are associated with an increased mortality. Here, virus infiltration may lead to a cytokine storm that potently activates neutrophils and leads to massive neutrophil infiltration into the lung and NET formation. The resulting NETs presumably activate platelets and coagulation factors, further contributing to the subsequent emergence of microthrombi in pulmonary capillaries. In this review, we will discuss the interplay between platelets and NETs and the potential of this alliance to influence the course of inflammatory diseases. A better understanding of the underlying molecular mechanisms and the identification of treatment targets is of utmost importance to increase patients’ survival and improve the clinical outcome.

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Section: The Pathophysiological Influence Of Platelet-net Interplay I...mentioning

confidence: 99%

Platelets in the NETworks interweaving inflammation and thrombosis

2022

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“…EETs have recently been shown to have a role in the pathogenesis of ANCA-associated vasculitis (AAV) [ 223 ]. In a study of 35 patients with AAV ([ 10 ] EGPA, [ 13 ] MPA, [ 12 ] GPA), those patients with EGPA only had significant serum cell free nuclear DNA and cell free mitochondrial DNA that associated with disease activity.…”

Section: Extracellular Traps Are No Longer the Strict Domain Of Neutr...mentioning

confidence: 99%

The Expanding Role of Extracellular Traps in Inflammation and Autoimmunity: The New Players in Casting Dark Webs

Huang

O’Sullivan

2022

IJMS

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The first description of a new form of neutrophil cell death distinct from that of apoptosis or necrosis was discovered in 2004 and coined neutrophil extracellular traps “(NETs)” or “NETosis”. Different stimuli for NET formation, and pathways that drive neutrophils to commit to NETosis have been elucidated in the years that followed. Critical enzymes required for NET formation have been discovered and targeted therapeutically. NET formation is no longer restricted to neutrophils but has been discovered in other innate cells: macrophages/monocytes, mast Cells, basophils, dendritic cells, and eosinophils. Furthermore, extracellular DNA can also be extruded from both B and T cells. It has become clear that although this mechanism is thought to enhance host defense by ensnaring bacteria within large webs of DNA to increase bactericidal killing capacity, it is also injurious to innocent bystander tissue. Proteases and enzymes released from extracellular traps (ETs), injure epithelial and endothelial cells perpetuating inflammation. In the context of autoimmunity, ETs release over 70 well-known autoantigens. ETs are associated with pathology in multiple diseases: lung diseases, vasculitis, autoimmune kidney diseases, atherosclerosis, rheumatoid arthritis, cancer, and psoriasis. Defining these pathways that drive ET release will provide insight into mechanisms of pathological insult and provide potential therapeutic targets.

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“…Because increased levels of cell-free mtDNA are also associated with several other inflammatory diseases-e.g., granulomatosis with polyangiitis (Hashimoto et al, 2021), further intensive research on the pro-inflammatory role of mtDNA should be conducted.…”

Section: Rheumatoid Arthritismentioning

confidence: 99%

Role of Mitochondrial Nucleic Acid Sensing Pathways in Health and Patho-Physiology

Chowdhury

Witte

Aich

2022

Front. Cell Dev. Biol.

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Mitochondria, in symbiosis with the host cell, carry out a wide variety of functions from generating energy, regulating the metabolic processes, cell death to inflammation. The most prominent function of mitochondria relies on the oxidative phosphorylation (OXPHOS) system. OXPHOS heavily influences the mitochondrial-nuclear communication through a plethora of interconnected signaling pathways. Additionally, owing to the bacterial ancestry, mitochondria also harbor a large number of Damage Associated Molecular Patterns (DAMPs). These molecules relay the information about the state of the mitochondrial health and dysfunction to the innate immune system. Consequently, depending on the intracellular or extracellular nature of detection, different inflammatory pathways are elicited. One group of DAMPs, the mitochondrial nucleic acids, hijack the antiviral DNA or RNA sensing mechanisms such as the cGAS/STING and RIG-1/MAVS pathways. A pro-inflammatory response is invoked by these signals predominantly through type I interferon (T1-IFN) cytokines. This affects a wide range of organ systems which exhibit clinical presentations of auto-immune disorders. Interestingly, tumor cells too, have devised ingenious ways to use the mitochondrial DNA mediated cGAS-STING-IRF3 response to promote neoplastic transformations and develop tumor micro-environments. Thus, mitochondrial nucleic acid-sensing pathways are fundamental in understanding the source and nature of disease initiation and development. Apart from the pathological interest, recent studies also attempt to delineate the structural considerations for the release of nucleic acids across the mitochondrial membranes. Hence, this review presents a comprehensive overview of the different aspects of mitochondrial nucleic acid-sensing. It attempts to summarize the nature of the molecular patterns involved, their release and recognition in the cytoplasm and signaling. Finally, a major emphasis is given to elaborate the resulting patho-physiologies.

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Increased Circulating Cell-Free DNA in Eosinophilic Granulomatosis With Polyangiitis: Implications for Eosinophil Extracellular Traps and Immunothrombosis

Cited by 30 publications

References 60 publications

Platelets in the NETworks interweaving inflammation and thrombosis

Platelets in the NETworks interweaving inflammation and thrombosis

The Expanding Role of Extracellular Traps in Inflammation and Autoimmunity: The New Players in Casting Dark Webs

Role of Mitochondrial Nucleic Acid Sensing Pathways in Health and Patho-Physiology

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