NEUTROPHIL EXTRACELLULAR TRAPS: NEW ASPECTS

Neutrophils are the first line of defense against invading pathogens in the focus of inflammation, where they use effector functions such as phagocytosis, degranulation and formation of reactive oxygen species (ROS). In 2004, Arturo Zychlinsky described an additional neutrophil effector function - the release of neutrophil extracellular traps or NETs. NETs consist of the modified chromatin “decorated” with bactericidal proteins from granules, nucleus, and cytoplasm. The release of NETs can be activated by a variety of physiological and pharmacological stimuli, and depends on the formation of ROS, the main source of which is enzymatic complex NADPH oxidase. In the process of NET formation, bactericidal granule components exit from granules into cytoplasm, the modification of histones leading to chromatin decondensation, the destruction of the nuclear envelope and cytoplasmic membrane, and the extrusion of chromatin outside the cell are taking place. However, the uncontrolled NET release is a provoking factor in the development of various inflammatory and autoimmune diseases. NETs have been discovered at autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, psoriasis, and vasculitis;NETs are involved in the pathogenesis of cardiovascular, pulmonary, and oncological diseases. In this review, the basic molecular mechanisms of NETs formation, as well as their role in the physiological processes and pathogenesis of a number of diseases including COVID-19 are discussed. Нейтрофилы являются «первой линией» защиты от патогенов в очаге воспаления, где они используют такие эффекторные функции, как фагоцитоз, дегрануляцию и образование активных форм кислорода (АФК). В 2004 г. Артуро Циклински охарактеризовал еще одну эффекторную функцию нейтрофилов - выброс нейтрофильных внеклеточных ловушек, или NET (neutrophil extracellular traps). NET представляют собой модифицированный хроматин, «декорированный» бактерицидными белками гранул, ядра и цитоплазмы. Выброс NET может активироваться разнообразными физиологическими и фармакологическими стимулами и зависит от АФК, основным источником которых является NADPH-оксидаза. В процессе активации NET происходят выход бактерицидных компонентов гранул в цитоплазму, модификация гистонов, ведущая к деконденсации хроматина, разрушение ядерной оболочки и цитоплазматической мембраны при участии белка газдермина D и, наконец, выброс хроматина за пределы клетки. Вместе с тем, неконтролируемое образование NET является провоцирующим фактором развития многих воспалительных и аутоиммунных заболеваний. NET были обнаружены при таких аутоиммунных заболеваниях, как системная красная волчанка, ревматоидный артрит, псориаз и васкулиты;NET участвуют в патогенезе сердечно-сосудистых, легочных и онкологических заболеваний. В настоящем обзоре обсуждаются основные представления о механизмах образования NET, а также их роль в физиологических процессах и патогенезе ряда заболеваний, включая COVID-19.

Neutrophil Extracellular Traps: New Aspects.

Neutrophils are the "first line" of defense against pathogens in the locus of inflammation, where they use effector functions such as phagocytosis, degranulation, and formation of reactive oxygen species (ROS). In 2004, Artuto Zychlinsky characterized one more neutrophil effector function-the release of neutrophil extracellular traps (or NETs). NETs are a modified chromatin "decorated" by bactericidal proteins of granules, nucleus, and cytoplasm. The release of NETs can be activated by diverse physiological and pharmacological stimuli and depends on ROS, for which NADPH oxidase is the main source. In the process of NET formation, the release of bactericidal components of granules into the cytoplasm, modification of histones leading to chromatin decondensation, destruction of the nuclear envelope and cytoplasmic membrane with the involvement of gasdermin D protein, and, finally, the release of chromatin outside the cell occurs. At the same time, uncontrolled formation of NETs is a provoking factor in the development of many inflammatory and autoimmune diseases. NETs were found at autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, psoriasis, and vasculitis; NETs are involved in the pathogenesis of cardiovascular, pulmonary, and oncological diseases. In this review, the main ideas about the mechanisms of NET formation, as well as their role in physiological processes and pathogenesis of a number of diseases (including COVID-19), are discussed.

NETosis: Molecular Mechanisms, Role in Physiology and Pathology.

NETosis is a program for formation of neutrophil extracellular traps (NETs), which consist of modified chromatin decorated with bactericidal proteins from granules and cytoplasm. Various pathogens, antibodies and immune complexes, cytokines, microcrystals, and other physiological stimuli can cause NETosis. Induction of NETosis depends on reactive oxygen species (ROS), the main source of which is NADPH oxidase. Activation of NADPH oxidase depends on increase in the concentration of Ca2+ in the cytoplasm and in some cases on the generation of ROS in mitochondria. NETosis includes release of the granule components into the cytosol, modification of histones leading to chromatin decondensation, destruction of the nuclear envelope, as well as formation of pores in the plasma membrane. In this review, basic mechanisms of NETosis, as well as its role in the pathogenesis of some diseases including COVID-19 are discussed.

NETosis: MOLECULAR MECHANISMS, ROLE IN PHYSIOLOGY AND PATHOLOGY

NETosis is a program for formation of neutrophil extracellular traps (NETs), which consist of modified chromatin decorated with bactericidal proteins from granules and cytoplasm. Various pathogens, antibodies and immune complexes, cytokines, microcrystals, and other physiological stimuli can cause NETosis. Induction of NETosis depends on reactive oxygen species (ROS), the main source of which is NADPH oxidase. Activation of NADPH oxidase depends on increase in the concentration of Ca²⁺ in the cytoplasm and in some cases on the generation of ROS in mitochondria. NETosis includes release of the granule components into the cytosol, modification of histones leading to chromatin decondensation, destruction of the nuclear envelope, as well as formation of pores in the plasma membrane. In this review, basic mechanisms of NETosis, as well as its role in the pathogenesis of some diseases including COVID-19 are discussed. НЕТоз - это программа образования нейтрофильных внеклеточных ловушек или NET (neutrophil extracellular traps), состоящих из модифицированного хроматина и связанных с ним бактерицидных белков гранул и цитоплазмы. НЕТоз могут вызывать различные патогены, антитела и иммунные комплексы, цитокины, микрокристаллы и другие физиологические стимулы. Индукция НЕТоза зависит от активных форм кислорода (АФК), основным источником которых служит NADPH-оксидаза. Активация NADPH-оксидазы зависит от повышения концентрации Са²⁺ в цитоплазме и в некоторых случаях от генерации АФК в митохондриях. В процессе НЕТоза происходит выход компонентов гранул в цитозоль, модификация гистонов, ведущая к деконденсации хроматина, разрушение ядерной оболочки, а также образование пор в плазматической мембране. В обзоре обсуждаются основные представления о механизмах НЕТоза, а также роль НЕТоза в патогенезе некоторых заболеваний, включая COVID-19.