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Release of neutrophil extracellular traps by neutrophils stimulated with antiphospholipid antibodies: a newly identified mechanism of thrombosis in the antiphospholipid syndrome.

ABSTRACT: Antiphospholipid antibodies (aPL), especially those targeting ?2 -glycoprotein I (?2 GPI), are well known to activate endothelial cells, monocytes, and platelets, with prothrombotic implications. In contrast, the interaction of aPL with neutrophils has not been extensively studied. Neutrophil extracellular traps (NETs) have recently been recognized as an important activator of the coagulation cascade, as well as an integral component of arterial and venous thrombi. This study was undertaken to determine whether aPL activate neutrophils to release NETs, thereby predisposing to the arterial and venous thrombosis inherent in the antiphospholipid syndrome (APS).Neutrophils, sera, and plasma were prepared from patients with primary APS (n?=?52) or from healthy volunteers and characterized. No patient had concomitant systemic lupus erythematosus.Sera and plasma from patients with primary APS had elevated levels of both cell-free DNA and NETs, as compared to healthy volunteers. Freshly isolated neutrophils from patients with APS were predisposed to high levels of spontaneous NET release. Further, APS patient sera, as well as IgG purified from APS patients, stimulated NET release from control neutrophils. Human aPL monoclonal antibodies, especially those targeting ?2 GPI, also enhanced NET release. The induction of APS NETs was abrogated with inhibitors of reactive oxygen species formation and Toll-like receptor 4 signaling. Highlighting the potential clinical relevance of these findings, APS NETs promoted thrombin generation.Our findings indicate that NET release warrants further investigation as a novel therapeutic target in APS.

SUBMITTER: Yalavarthi S

PROVIDER: S-EPMC4626310 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Release of neutrophil extracellular traps by neutrophils stimulated with antiphospholipid antibodies: a newly identified mechanism of thrombosis in the antiphospholipid syndrome.

Yalavarthi Srilakshmi S Gould Travis J TJ Rao Ashish N AN Mazza Levi F LF Morris Alexandra E AE Núñez-Álvarez Carlos C Hernández-Ramírez Diego D Bockenstedt Paula L PL Liaw Patricia C PC Cabral Antonio R AR Knight Jason S JS

Arthritis & rheumatology (Hoboken, N.J.) 20151101 11

<h4>Objective</h4>Antiphospholipid antibodies (aPL), especially those targeting β2 -glycoprotein I (β2 GPI), are well known to activate endothelial cells, monocytes, and platelets, with prothrombotic implications. In contrast, the interaction of aPL with neutrophils has not been extensively studied. Neutrophil extracellular traps (NETs) have recently been recognized as an important activator of the coagulation cascade, as well as an integral component of arterial and venous thrombi. This study w ...[more]

PMID: 26097119

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Project description:The release of neutrophil extracellular traps (NETs), either during "suicidal" or "vital" NETosis, represents an important strategy of neutrophils to combat Gram-negative bacteria. Lipopolysaccharide (LPS), a major component of the outer membrane of Gram-negative bacteria, is a reported stimulus for NET formation. Although it is widely acknowledged that the structural diversity in LPS structures can elicit heterogeneous immune responses, species- and serotype-specific differences in the capacity of LPS to trigger NET formation have not yet been investigated. In the present study, we compared the NET-inducing potential of LPS derived from Escherichia coli (serotypes O55:B5, O127:B8, O128:B12, O111:B4, and O26:B6), Salmonella enterica (serotype enteritidis), and Pseudomonas aeruginosa (serotype 10), under platelet-free and platelet-rich conditions in vitro, and in whole blood ex vivo. Here, we demonstrate that under serum- and platelet-free conditions, mimicking tissue circumstances, neutrophils discriminate between LPS of different bacterial sources and selectively release NETs only in response to LPS derived from E. coli O128:B12 and P. aeruginosa 10, which both induced "suicidal" NETosis in an autophagy- and reactive oxygen species (ROS)-dependent, but TLR4-independent manner. Intriguingly, in whole blood cultures ex vivo, or in vitro in the presence of platelets, all LPS serotypes induced "vital" NET formation. This platelet-dependent release of NETs occurred rapidly without neutrophil cell death and was independent from ROS formation and autophagy but required platelet TLR4 and CD62P-dependent platelet-neutrophil interactions. Taken together, our data reveal a complex interplay between neutrophils and LPS, which can induce both "suicidal" and "vital" NETosis, depending on the bacterial origin of LPS and the presence or absence of platelets. Our findings suggest that LPS sensing by neutrophils may be a critical determinant for restricting NET release to certain Gram-negative bacteria only, which in turn may be crucial for minimizing unnecessary NET-associated immunopathology.

Dataset Information

Release of neutrophil extracellular traps by neutrophils stimulated with antiphospholipid antibodies: a newly identified mechanism of thrombosis in the antiphospholipid syndrome.

Publications

Release of neutrophil extracellular traps by neutrophils stimulated with antiphospholipid antibodies: a newly identified mechanism of thrombosis in the antiphospholipid syndrome.

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