Neutrophil-derived vesicles control complement activation to facilitate inflammation resolution

Alan Y Hsu¹, Qingxiang Huang², Xiong Pi³, Jianing Fu³, Krishnan Raghunathan⁴, Laxman Ghimire¹, Arumugam Balasubramanian¹, Xuemei Xie¹, Hongbo Yu⁵, Fabien Loison¹, Viraga Haridas⁶, Jiali Zha¹, Fei Liu¹, Shin-Young Park¹, Kamal Bagale⁷, Qian Ren², Yuping Fan², Yi Zheng⁸, Jose A Cancelas⁹, Li Chai¹, Sean R Stowell¹, Kanchao Chen², Rong Xu¹, Xiaoxue Wang¹⁰, Yuanfu Xu², Lianghui Zhang⁷, Tao Cheng², Fengxia Ma², Jay R Thiagarajah¹¹, Hao Wu³, Sizhou Feng¹², Hongbo R Luo¹³

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: doctor_szhfeng@163.com.
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: hrluo@bwh.harvard.edu.

PMID: 39938514
PMCID: PMC11934499 (available on 2026-03-20)
DOI: 10.1016/j.cell.2025.01.021

Neutrophil-derived vesicles control complement activation to facilitate inflammation resolution

Alan Y Hsu et al. Cell. 2025.

. 2025 Mar 20;188(6):1623-1641.e26.

doi: 10.1016/j.cell.2025.01.021. Epub 2025 Feb 11.

Authors

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: doctor_szhfeng@163.com.
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: hrluo@bwh.harvard.edu.

PMID: 39938514
PMCID: PMC11934499 (available on 2026-03-20)
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.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests The authors declare no competing interests.

References

1. Kolaczkowska E, and Kubes P (2013). Neutrophil recruitment and function in health and inflammation. Nat. Rev. Immunol 13, 159–175. 10.1038/nri3399. - DOI - PubMed
1. Burn GL, Foti A, Marsman G, Patel DF, and Zychlinsky A (2021). The neutrophil. Immunity 54, 1377–1391. 10.1016/j.immuni.2021.06.006. - DOI - PubMed
1. Laforge M, Elbim C, Frère C, Hémadi M, Massaad C, Nuss P, Benoliel JJ, and Becker C (2020). Tissue damage from neutrophil-induced oxidative stress in COVID-19. Nat. Rev. Immunol 20, 515–516. 10.1038/s41577-020-0407-1. - DOI - PMC - PubMed
1. Weiss SJ (1989). Tissue destruction by neutrophils. N. Engl. J. Med 320, 365–376. 10.1056/NEJM198902093200606. - DOI - PubMed
1. Greenlee-Wacker MC (2016). Clearance of apoptotic neutrophils and resolution of inflammation. Immunol. Rev 273, 357–370. 10.1111/imr.12453. - DOI - PMC - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Neutrophil-derived vesicles control complement activation to facilitate inflammation resolution

Affiliations

Neutrophil-derived vesicles control complement activation to facilitate inflammation resolution

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Molecular Biology Databases

Miscellaneous