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Soluble CD13 is a potential mediator of neutrophil-induced thrombogenic inflammation in SARS-CoV-2 infection

  1. Author:
    Tsou, Pei-Suen
    Ali, Ramadan A
    Lu, Chenyang
    Sule, Gautam
    Carmona-Rivera, Carmelo
    Lucotti, Serena
    Ikari, Yuzo
    Wu, Qi
    Campbell, Phillip
    Gurrea-Rubio, Mikel
    Maeda, Kohei
    Fox, Sharon E
    Brodie, William D
    Mattichak, Megan N
    Foster, Caroline
    Tambralli, Ajay
    Yalavarthi, Srilakshmi
    Amin, M Asif
    Kmetova, Katarina
    Mazetto Fonseca, Bruna
    Chong, Emily
    Zuo, Yu
    Maile, Michael
    Imberti, Luisa
    Caruso, Arnaldo
    Caccuri, Francesca
    Quaresima, Virginia
    Sottini, Alessandra
    Kuhns,Douglas
    Fink,Danielle
    Castagnoli, Riccardo
    Delmonte, Ottavia
    Kenney, Heather
    Zhang, Yu
    Magliocco, Mary
    Su, Helen C
    Notarangelo, Luigi D
    Zemans, Rachel L
    Mao-Draayer, Yang
    Matei, Irina
    Salvatore, Mirella
    Lyden, David C
    Kanthi, Yogendra
    Kaplan, Mariana J
    Knight, Jason S
    Fox, David A

  2. Author Address

    Division of Rheumatology, Department of Internal Medicine and Clinical Auto, University of Michigan, Ann Arbor, United States of America., Division of Rheumatology, Department of Internal Medicine, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China., Systemic Autoimmunity Branch, National Institute of Arthritis and Musculosk, NIH, Bethesda, United States of America., Department of Pediatrics, Weill Cornell Medical College, New York, United States of America., Department of Pathology, Louisiana State University, Health Sciences Center, New Orleans, United States of America., Department of Anesthesiology, University of Michigan, Ann Arbor, United States of America., Section of Microbiology, University of Brescia, Brescia, Italy., Clinical Chemistry Laboratory, ASST Spedali Civili of Brescia, Brescia, Italy., Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, United States of America., Division of Intramural Research, National Institute of Allergy and Infectio, NIH, Bethesda, United States of America., Division of Pulmonary, Department of Internal Medicine; Program in Cellular, University of Michigan, Ann Arbor, United States of America., Multiple Sclerosis Center of Excellence, Arthritis and Clinical Immunology , Oklahoma Medical Research Foundation, Oklahoma City, United States of America., Joan and Sanford I. Weill Department of Medicine and Department of Populati, Weill Cornell Medical College, New York, United States of America., Division of Intramural Research, National Heart, Lung and Blood Institute, NIH, Bethesda, United States of America.,
    1. Year: 2025
    2. Date: Apr 01
    3. Epub Date: 2025 04 01
  2. Journal: JCI Insight
  4. Type of Article: Article
  5. Article Number: e184975
  1. Abstract:

    The soluble variant of the ectopeptidase CD13 (sCD13), released from the cell surface by matrix metalloproteinase 14 (MMP14), is a potent pro-inflammatory mediator, displaying chemotactic, angiogenic, and arthritogenic properties through bradykinin receptor B1 (B1R). We reveal a link between sCD13 and amplified neutrophil-mediated inflammatory responses in SARS-CoV-2 infection. sCD13 was markedly elevated in COVID-19 patients and correlated with disease severity, variants, ethnicity, inflammation markers, and NETosis. Neutrophils treated with sCD13 showed heightened NETosis and chemotaxis which were inhibited by sCD13 receptor blockade. Meanwhile sCD13 did not induce platelet aggregation. Single-cell analysis of COVID-19 lungs revealed co-expression of CD13 and MMP14 by various cell types, and higher CD13 expression compared to controls. Neutrophils with high CD13 mRNA were enriched for genes associated with immaturity, though CD13 protein expression was lower. Histological examination of COVID-19 lungs revealed CD13-positive leukocytes trapped in vessels with fibrin thrombi. Flow cytometry confirmed the presence of B1R and a second sCD13 receptor, protease-activated receptor 4, on monocytes and neutrophils. These findings identify sCD13 as a potential instigator of COVID-19-associated NETosis, potentiating vascular stress and thromboembolic complications. The potent pro-inflammatory effects of sCD13 may contribute to severe COVID-19, suggesting that sCD13 and its receptors might be therapeutic targets.

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External Sources

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  2. DOI: 10.1172/jci.insight.184975
  3. PMID: 40168094
  4. PII : 184975

Library Notes

  1. Fiscal Year: FY2024-2025
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