NETosis: Molecular Mechanisms, Role in Physiology and Pathology

Vorobjeva, N.V.; Chernyak, Boris V.

doi:10.1134/s0006297920100065

Cited by 296 publications

(286 citation statements)

References 109 publications

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“…Although NETs play a beneficial role in the defense of their host from pathogens, extended inflammation connected with their presence may cause a cascade of unfavorable reactions. The example of such reactions is the production of antibodies against the host’s DNA (autoimmunization), damage to surrounding tissue, or the occurrence of atherothrombotic events [ 3 , 4 , 7 , 20 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ].…”

Section: Neutrophil Extracellular Trapsmentioning

confidence: 99%

Significance of NETs Formation in COVID-19

Janiuk

Jabłońska

Garley

2021

Cells

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Severe contagious respiratory disease—COVID-19—caused by the SARS-CoV-2 coronavirus, can lead to fatal respiratory failure associated with an excessive inflammatory response. Infiltration and spread of SARS-CoV-2 are based on the interaction between the virus’ structural protein S and the cell’s receptor–angiotensin-converting enzyme 2 (ACE2), with the simultaneous involvement of human trans-membrane protease, serine 2 (TMPRSS2). Many scientific reports stress the importance of elevated recruitment and activity of neutrophils, which can form extracellular neutrophil traps (NETs) playing a significant role in the mechanism of combating pathogens, in the pathogenesis of COVID-19. Excessive generation of NETs during prolonged periods of inflammation predisposes for the occurrence of undesirable reactions including thromboembolic complications and damage to surrounding tissues and organs. Within the present manuscript, we draw attention to the impact of NET generation on the severe course of COVID-19 in patients with concurrent cardiovascular and metabolic diseases. Additionally, we indicate the necessity to explore not only the cellular but also the molecular bases of COVID-19 pathogenesis, which may aid the development of dedicated therapies meant to improve chances for the successful treatment of patients. We also present new directions of research into medications that display NETs formation regulatory properties as potential significant therapeutic strategies in the progress of COVID-19.

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Section: Neutrophil Extracellular Trapsmentioning

confidence: 99%

Significance of NETs Formation in COVID-19

Janiuk

Jabłońska

Garley

2021

Cells

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“…Treatment with DNase can significantly destroy the structure of NETs ( Dąbrowska et al., 2016 ). The formation of NETs often leads to death of neutrophil, and this process is called NETosis ( Vorobjeva and Chernyak, 2020 ). NETs can be formed in various parts of the body, and NETs can be released wherever neutrophils exist.…”

Section: The Formation Of Netsmentioning

confidence: 99%

Review: The Emerging Role of Neutrophil Extracellular Traps in Sepsis and Sepsis-Associated Thrombosis

Chen

Zhang

et al. 2021

Front. Cell. Infect. Microbiol.

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Patients with sepsis commonly suffer from coagulation dysfunction and lead to the formation of thrombus. During the development of sepsis, neutrophils migrate from the circulating blood to infected tissues and mediate the formation of neutrophil extracellular traps (NETs) that kill pathogens. However, the overactivation of neutrophils can promote the formation of immunothrombosis and even cause disseminated intravascular coagulation (DIC), which damages microcirculation. The outcome of sepsis depends on early recognition and intervention, so clinical evaluation of NETs function may be a valuable biomarker for early diagnosis of sepsis. The interaction of NETs with platelets, complement, and endothelium mediates the formation of immunothrombosis in sepsis. Inhibiting the formation of NETs is also considered to be one of the potential treatments for sepsis. In this review, we will discuss the key role of neutrophils and NETs in sepsis and septic thrombosis, in order to reveal new mechanisms for thrombosis treatment of sepsis.

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“…Furthermore, since Ly6G neg MDSCs have been described previously, and as given the frequently reported limited depleting efficacy of anti-Ly6G ab; it is likely that the present report showing the sequence: 1) neutrophil aging, 2) anti-Ly6G internalization and 3) depletion resistance, 4) neutrophil gain of function; may apply for other inflammatory/cancer models. 24 Finally, given the emerging importance of neutrophil extracellular traps (NETs) in cancer 43 and considering ANCA may intrinsically promote the NET formation, 44 , 45 it would be interesting to address either administration of anti-Ly6G recapitulates this physiology and to question the role of NET in this primary lung cancer model, especially in the context of radiation-therapy.…”

Section: Discussionmentioning

confidence: 99%

Anti-Ly6G binding and trafficking mediate positive neutrophil selection to unleash the anti-tumor efficacy of radiation therapy

et al. 2021

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The anti-Ly6G antibody is used to deplete Ly6G pos neutrophils and study their role in diverse pathologies. However, depletion is never absolute, as Ly6G low neutrophils resistant to depletion rapidly emerge. Studying the functionality of these residual neutrophils is necessary to interpret anti-Ly6G-based experimental designs. In vitro , we found anti-Ly6G binding induced Ly6G internalization, surface Ly6G paucity, and primed the oxidative burst of neutrophils upon TNF α co-stimulation. In vivo , we found neutrophils resistant to anti-Ly6G depletion exhibited anti-neutrophil-cytoplasmic-antibodies. In the pre-clinical Kras Lox-STOP-Lox-G12D/WT ; Trp53 Flox/Flox mouse lung tumor model, abnormal neutrophil accumulation and aging was accompanied with an N2-like SiglecF pos polarization and ly6g downregulation. Consequently, SiglecF pos neutrophils exposed to anti-Ly6G reverted to Ly6G low and were resistant to depletion. Noting that anti-Ly6G mediated neutrophil depletion alone had no anti-tumor effect, we found a long-lasting rate of tumor regression (50%) by combining anti-Ly6G with radiation-therapy, in this model reputed to be refractory to standard anticancer therapies. Mechanistically, anti-Ly6G regulated neutrophil aging while radiation-therapy enhanced the homing of anti-Ly6G-boundSiglecF neg neutrophils to tumors. This anti-tumor effect was recapitulated by G-CSF administration prior to RT and abrogated with an anti-TNFα antibody co-administration. In summary, we report that incomplete depletion of neutrophils using targeted antibodies can intrinsically promote their oxidative activity. This effect depends on antigen/antibody trafficking and can be harnessed locally using select delivery of radiation-therapy to impair tumor progression. This underutilized aspect of immune physiology may be adapted to expand the scope of neutrophil-related research.

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NETosis: Molecular Mechanisms, Role in Physiology and Pathology

Cited by 296 publications

References 109 publications

Significance of NETs Formation in COVID-19

Significance of NETs Formation in COVID-19

Review: The Emerging Role of Neutrophil Extracellular Traps in Sepsis and Sepsis-Associated Thrombosis

Anti-Ly6G binding and trafficking mediate positive neutrophil selection to unleash the anti-tumor efficacy of radiation therapy

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