title: Neutrophils Discriminate between Lipopolysaccharides of Different Bacterial Sources and Selectively Release Neutrophil Extracellular Traps.
abstract: 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 fromEscherichia coli(serotypesO55:B5, O127:B8, O128:B12, O111:B4, andO26:B6),Salmonella enterica(serotypeenteritidis), andPseudomonas aeruginosa(serotype10), under platelet-free and platelet-rich conditionsin vitro, and in whole bloodex 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 fromE. coli O128:B12andP. aeruginosa 10, which both induced "suicidal" NETosis in an autophagy- and reactive oxygen species (ROS)-dependent, but TLR4-independent manner. Intriguingly, in whole blood culturesex vivo, orin vitroin 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.
authors.affiliation: Department of Nephrology, Radboud University Medical Center , Nijmegen , Netherlands.
authors.forename: Elmar
authors.initials: E
authors.lastname: Pieterse
authors.affiliation: Department of Nephrology, Radboud University Medical Center , Nijmegen , Netherlands.
authors.forename: Nils
authors.initials: N
authors.lastname: Rother
authors.affiliation: Department of Nephrology, Radboud University Medical Center , Nijmegen , Netherlands.
authors.forename: Cansu
authors.initials: C
authors.lastname: Yanginlar
authors.affiliation: Department of Nephrology, Radboud University Medical Center , Nijmegen , Netherlands.
authors.forename: Luuk B
authors.initials: LB
authors.lastname: Hilbrands
authors.affiliation: Department of Nephrology, Radboud University Medical Center , Nijmegen , Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: van der Vlag
keywords: NETosis; cell death; lipopolysaccharides; neutrophil extracellular traps; platelets