Elongated neutrophil-derived structures are blood-borne microparticles formed by rolling neutrophils during sepsis

Author:

Marki Alex1ORCID,Buscher Konrad12ORCID,Lorenzini Cristina13ORCID,Meyer Matthew1ORCID,Saigusa Ryosuke1ORCID,Fan Zhichao14ORCID,Yeh Yi-Ting5ORCID,Hartmann Nadine1ORCID,Dan Jennifer M.16ORCID,Kiosses William B.1ORCID,Golden Gregory J.7ORCID,Ganesan Rajee8ORCID,Winkels Holger1ORCID,Orecchioni Marco1ORCID,McArdle Sara1ORCID,Mikulski Zbigniew1ORCID,Altman Yoav9ORCID,Bui Jack10ORCID,Kronenberg Mitchell1ORCID,Chien Shu11ORCID,Esko Jeffrey D.7ORCID,Nizet Victor12ORCID,Smalley David13ORCID,Roth Johannes11ORCID,Ley Klaus114ORCID

Affiliation:

1. La Jolla Institute for Immunology, La Jolla, CA

2. Division of General Internal Medicine, Nephrology, and Rheumatology, Department of Medicine D, University Hospital Muenster, Muenster, Germany

3. Laboratory of Immunobiology, Federal University of Santa Catarina, Florianopolis, Santa Catarina, Brazil

4. Department of Immunology, University of Connecticut Health Center, Farmington, CT

5. Mechanical and Aerospace Engineering, University of California, San Diego, La Jolla, CA

6. Division of Infectious Diseases and Global Public Health, University of California, San Diego, La Jolla, CA

7. Department of Cellular and Molecular Medicine and Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA

8. Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC

9. Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA

10. Department of Pathology, University of California, San Diego, La Jolla, CA

11. Institute for Immunology, University of Muenster, Muenster, Germany

12. Department of Pediatrics and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA

13. Systems Mass Spectrometry Core, Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA

14. Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA

Abstract

Rolling neutrophils form tethers with submicron diameters. Here, we report that these tethers detach, forming elongated neutrophil-derived structures (ENDS) in the vessel lumen. We studied ENDS formation in mice and humans in vitro and in vivo. ENDS do not contain mitochondria, endoplasmic reticulum, or DNA, but are enriched for S100A8, S100A9, and 57 other proteins. Within hours of formation, ENDS round up, and some of them begin to present phosphatidylserine on their surface (detected by annexin-5 binding) and release S100A8–S100A9 complex, a damage-associated molecular pattern protein that is a known biomarker of neutrophilic inflammation. ENDS appear in blood plasma of mice upon induction of septic shock. Compared with healthy donors, ENDS are 10–100-fold elevated in blood plasma of septic patients. Unlike neutrophil-derived extracellular vesicles, most ENDS are negative for the tetraspanins CD9, CD63, and CD81. We conclude that ENDS are a new class of bloodborne submicron particles with a formation mechanism linked to neutrophil rolling on the vessel wall.

Funder

National Institutes of Health

American Heart Association

Tullie and Rickey Families SPARK Award

Deutsche Forschungsgemeinschaft

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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