P-selectin promotes neutrophil extracellular trap formation in mice

Etulain, Julia; Martinod, Kimberly; Wong, Siu Ling; Cifuni, Stephen M.; Schattner, Mirta; Wagner, Denisa D.

doi:10.1182/blood-2015-01-624023

Cited by 407 publications

(365 citation statements)

References 27 publications

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“…21,23,24 Moreover, tumors are prothrombotic and the interaction of intratumoral neutrophils with the activated endothelium or platelets via P-selectin would also induce NETosis. 25 Our work and that of others 15 indicates that a closer monitoring of neutrophil counts and activation and a deeper understanding of the tumor environment and the factors that drive NETosis should be of prime importance in the fight against cancer.…”

Section: Discussionmentioning

confidence: 99%

Priming of neutrophils toward NETosis promotes tumor growth

et al. 2016

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Neutrophils play a major role in cancer biology and both pro-and antitumoral functions of tumorinfiltrating neutrophils have been described. We have shown that tumors, by releasing G-CSF into the bloodstream, prime circulating neutrophils to form neutrophil extracellular traps (NETs) and we have detected the presence of NETs within the tumor microenvironment. Here, we report, using PAD4-deficient mice with a defect in neutrophil chromatin decondensation and NET formation, that the priming of neutrophils toward NETosis favors tumor growth. Interestingly, in a tumor model that does not release G-CSF and in which neutrophils are not primed for NETosis, PAD4-deficiency did not reduce tumor growth. However, supplying exogenous G-CSF to the wild-type (WT) host promoted intratumoral NETosis and tumor growth. Taken together, our results suggest that the priming of neutrophils for NETosis by the tumor or its environment leads to the accumulation of intratumoral NETs and a growth advantage to the tumor. Our work unveiled a pro-tumoral role for NETs which strengthens their potential as a new target in the fight against cancer.

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Section: Discussionmentioning

confidence: 99%

Priming of neutrophils toward NETosis promotes tumor growth

et al. 2016

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“…Strategies that aim to limit the release of NETs are only now beginning to emerge (12,24,48). We have previously proposed that targeting immune inhibitory receptors to arrest NET formation could be beneficial in the context of autoimmunity (38).…”

Section: Discussionmentioning

confidence: 99%

Signal Inhibitory Receptor on Leukocytes-1 Limits the Formation of Neutrophil Extracellular Traps, but Preserves Intracellular Bacterial Killing

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Naccache

et al. 2016

The Journal of Immunology

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In response to microbial invasion, neutrophils release neutrophil extracellular traps (NETs) to trap and kill extracellular microbes. Alternatively, NET formation can result in tissue damage in inflammatory conditions and may perpetuate autoimmune disease. Intervention strategies that are aimed at modifying pathogenic NET formation should ideally preserve other neutrophil antimicrobial functions. We now show that signal inhibitory receptor on leukocytes-1 (SIRL-1) attenuates NET release by human neutrophils in response to distinct triggers, including opsonized Staphylococcus aureus and inflammatory danger signals. NET release has different kinetics depending on the stimulus, and rapid NET formation is independent of NADPH oxidase activity. In line with this, we show that NET release and reactive oxygen species production upon challenge with opsonized S. aureus require different signaling events. Importantly, engagement of SIRL-1 does not affect bacterially induced production of reactive oxygen species, and intracellular bacterial killing by neutrophils remains intact. Thus, our studies define SIRL-1 as an intervention point of benefit to suppress NET formation in disease while preserving intracellular antimicrobial defense.

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“…6 Indeed, P-selectin-dependent NET formation was shown by the authors to be ROS dependent. 1 Therefore, soluble P-selectin may prime the neutrophil NADPH oxidase for NET formation. Finally, how do we explain the significant (although minor) fraction of circulating neutrophils in healthy humans that exist as heterotypic aggregates with platelets?…”

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confidence: 99%

“…1 They then show that prolonged iron deprivation by a chelator, deferasirox, reduces porphyrin overproduction and ineffective erythropoiesis and ameliorates symptoms in both the case and her affected sibling. The authors complement their clinical observation with in vitro investigations showing that erythropoietic precursor cells originating from the CEP cases have an improved survival in an iron-restricted environment.…”

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“…This map allows us to (1) have some idea of the fundamental biology underlying the disease, (2) define potential drug targets, and (3) refine outcome expectations, especially when there are no "knockout" therapies (like in chronic myeloid leukemia). The consequence is also the further subclassification of myeloid malignancies, thus making relatively rare diseases into extremely rare ones.…”

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confidence: 99%

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