Neutrophil-derived vesicles control complement activation to facilitate inflammation resolution

  • Cell. 2025 Mar 20;188(6):1623-1641.e26. doi: 10.1016/j.cell.2025.01.021.
Alan Y Hsu  1 ,  Qingxiang Huang  2 ,  Xiong Pi  3 ,  Jianing Fu  3 ,  Krishnan Raghunathan  4 ,  Laxman Ghimire  1 ,  Arumugam Balasubramanian  1 ,  Xuemei Xie  1 ,  Hongbo Yu  5 ,  Fabien Loison  1 ,  Viraga Haridas  6 ,  Jiali Zha  1 ,  Fei Liu  1 ,  Shin-Young Park  1 ,  Kamal Bagale  7 ,  Qian Ren  2 ,  Yuping Fan  2 ,  Yi Zheng  8 ,  Jose A Cancelas  9 ,  Li Chai  1 ,  Sean R Stowell  1 ,  Kanchao Chen  2 ,  Rong Xu  1 ,  Xiaoxue Wang  10 ,  Yuanfu Xu  2 ,  Lianghui Zhang  7 ,  Tao Cheng  2 ,  Fengxia Ma  2 ,  Jay R Thiagarajah  11 ,  Hao Wu  3 ,  Sizhou Feng  12 ,  Hongbo R Luo  13
Affiliations
  • 1. Department of Pathology, PhD Program in Immunology, Harvard Medical School, Boston, MA 02115, USA; Dana-Farber/Harvard Cancer Center, Boston, MA 02115, USA; Department of Pathology, Mass General Brigham, Boston, MA 02115, USA.
  • 2. State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.
  • 3. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 20115, USA.
  • 4. Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Harvard Medical School, Boston, MA 20115, USA.
  • 5. Department of Pathology and Laboratory Medicine, VA Boston Healthcare System, West Roxbury, Boston, MA 02132, USA.
  • 6. Flow and Imaging Cytometry Resources, Boston Children's Hospital, Boston, MA 02115, USA.
  • 7. Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
  • 8. Experimental Hematology and Cancer Biology Research, Cincinnati Children's Hospital Medical Center, Hoxworth Blood Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
  • 9. Experimental Hematology and Cancer Biology Research, Cincinnati Children's Hospital Medical Center, Hoxworth Blood Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Connell and O'Reilly Families Cell Manipulation Core Facility, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • 10. University of Chinese Academy of Sciences, Beijing 101408, China.
  • 11. Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Harvard Medical School, Boston, MA 20115, USA; Congenital Enteropathy Program, Boston Children's Hospital, PediCODE Consortium, Harvard Digestive Disease Center, Boston, MA, USA.
  • 12. State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China. Electronic address: [email protected].
  • 13. Department of Pathology, PhD Program in Immunology, Harvard Medical School, Boston, MA 02115, USA; Dana-Farber/Harvard Cancer Center, Boston, MA 02115, USA; Department of Pathology, Mass General Brigham, Boston, MA 02115, USA. Electronic address: [email protected].
PMID: 39938514 DOI: 10.1016/j.cell.2025.01.021
Abstract

Although subsets with immunosuppressive properties exist, neutrophils are typically known for their pro-inflammatory role and pathogen clearance capabilities. Here, we reveal that neutrophils can paradoxically aid in resolving inflammation by actively producing anti-inflammatory extracellular vesicles. These large aging-neutrophil-derived vesicles (LAND-Vs) do not fit into classical vesicle categorizations due to their specific size, structure, or biogenesis pathway. They are protected from efferocytotic clearance by phagocytes due to surface "do not eat me" signals and accumulate in the resolution phase of inflammation. CD55 on LAND-Vs exerts a robust, sustained anti-inflammatory effect by inhibiting complement 3 convertase, thereby reducing neutrophil recruitment and tissue damage. CD55+ LAND-Vs originate in ordered lipid raft domains, where CD55 accumulates asymmetrically during neutrophil aging, and are subsequently formed through RhoA-dependent budding. Collectively, LAND-V emerges as a pivotal physiological immunomodulator and showcases functions that transcend the limited lifespan of neutrophils, offering a therapeutic target for inflammatory and infectious diseases.

Keywords
CD55; COVID-19; aging; complement; do not eat me signal; extracellular vesicles; inflammation resolution; lung injury; neutrophils; pneumonia.
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