Soluble CD13 is a potential mediator of neutrophil-induced thrombogenic inflammation in SARS-CoV-2 infection
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 revealed a link between sCD13 and amplified neutrophil-mediated inflammatory responses in SARS-CoV-2 infection. sCD13 was markedly elevated in patients with COVID-19 and correlated with disease severity and variants, ethnicity, inflammation markers, and neutrophil extracellular trap formation (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 coexpression of CD13 and MMP14 by various cell types, and higher CD13 expression compared with 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 verified 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.
Authors
- Heather Kenney (ORCID: https://orcid.org/0009-0006-7009-2547)
- Francesca Caccuri (ORCID: https://orcid.org/0000-0002-1923-9033)
- Yu Zuo (ORCID: https://orcid.org/0000-0002-9303-7480)
- Michael D. Maile (ORCID: https://orcid.org/0000-0001-8236-3371)
- Pei‐Suen Tsou (ORCID: https://orcid.org/0000-0002-7149-9115)
- Mariana J. Kaplan (ORCID: https://orcid.org/0000-0003-2968-0815)
- Irina Matei (ORCID: https://orcid.org/0000-0002-5712-8430)
- Helen C. Su (ORCID: https://orcid.org/0000-0002-5582-9110)
- Douglas B. Kuhns (ORCID: https://orcid.org/0000-0002-9971-0760)
- Qi Wu (ORCID: https://orcid.org/0000-0002-2550-3769)
- Bruna Mazetto Fonseca
- David A. Fox (ORCID: https://orcid.org/0000-0002-0230-6607)
- Katarína Kmeťová (ORCID: https://orcid.org/0000-0002-2730-4587)
- Luigi Daniele Notarangelo (ORCID: https://orcid.org/0000-0002-8335-0262)
- Rachel L. Zemans (ORCID: https://orcid.org/0000-0003-3537-9869)
- Megan N. Mattichak (ORCID: https://orcid.org/0000-0002-1164-5176)
- Phillip L. Campbell
- Yang Mao‐Draayer (ORCID: https://orcid.org/0000-0001-6248-3480)
- Virginia Quaresima (ORCID: https://orcid.org/0000-0001-8858-3236)
- Ottavia M. Delmonte (ORCID: https://orcid.org/0000-0002-4772-0799)
- Srilakshmi Yalavarthi (ORCID: https://orcid.org/0009-0005-9128-572X)
- Ramadan A. Ali (ORCID: https://orcid.org/0000-0003-1507-1517)
- David Lyden (ORCID: https://orcid.org/0000-0003-0193-4131)
- Danielle Fink (ORCID: https://orcid.org/0000-0002-7502-7385)
- Arnaldo Caruso (ORCID: https://orcid.org/0000-0001-5178-566X)
- Riccardo Castagnoli (ORCID: https://orcid.org/0000-0003-0029-9383)
- Mirella Salvatore
- Yuzo Ikari (ORCID: https://orcid.org/0000-0002-4091-8882)
- Yogendra Kanthi (ORCID: https://orcid.org/0000-0002-5660-5194)
- Mikel Gurrea‐Rubio (ORCID: https://orcid.org/0000-0002-0478-1751)
- Gautam Sule
- Kohei Maeda (ORCID: https://orcid.org/0000-0003-4195-6183)
- Ajay Tambralli (ORCID: https://orcid.org/0000-0001-9056-9513)
- Mary Magliocco
- Sharon Fox (ORCID: https://orcid.org/0000-0002-0766-5393)
- William D. Brodie
- Carmelo Carmona‐Rivera (ORCID: https://orcid.org/0000-0002-7706-1464)
- Serena Lucotti (ORCID: https://orcid.org/0000-0003-1318-4761)
- Jason S. Knight (ORCID: https://orcid.org/0000-0003-0995-9771)
- Yu Zhang (ORCID: https://orcid.org/0000-0002-6904-0372)
- Chenyang Lu (ORCID: https://orcid.org/0000-0001-9128-6769)
- Alessandra Sottini (ORCID: https://orcid.org/0000-0001-5723-9619)
- Emily Chong
- Caroline Foster
- Luisa Imberti
- M. Asif Amin
Institutions
- Leidos (United States) (US)
- Sun Yat-sen University (CN)
- Universidade Estadual de Campinas (UNICAMP) (BR)
- Cornell University (US)
- University of Michigan (US)
- Oklahoma Medical Research Foundation (US)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (US)
- Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (IT)
- College Medical Center (US)
- National Heart, Lung, and Blood Institute (US)
- Michigan Medicine (US)
- National Institute of Allergy and Infectious Diseases (US)
- Third Affiliated Hospital of Sun Yat-sen University (CN)
- Louisiana State University Health Sciences Center New Orleans (US)
- University of Brescia (IT)
Publication Details
- Journal
- JCI Insight
- Published
- 2025-04-01
- DOI
- https://doi.org/10.1172/jci.insight.184975
- Citations
- 4
- Primary Topic
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 3.19
Funders
- U.S. Department of Defense
- University of Michigan
- Fundação de Amparo à Pesquisa do Estado de São Paulo
- National Institutes of Health
- College of Pharmacy, University of Michigan
- National Heart, Lung, and Blood Institute