Pei-Suen Tsou, University of Michigan, Ann Arbor, MI
Ramadan A. Ali, University of Michigan, Ann Arbor, MI
Chenyang Lu, Sun Yat-Sen University, Guangzhou, China
Gautam Sule, University of Michigan, Ann Arbor, MI
Carmelo Carmona-Rivera, NIH, Bethesda, MD
Serena Lucotti, Weill Cornell Medical College, New York, NY
Yuzo Ikari, University of Michigan, Ann Arbor, MI
Qi Wu, University of Michigan, Ann Arbor, MI
Phillip L. Campbell, University of Michigan, Ann Arbor, MI
Mikel Gurrea-Rubio, University of Michigan, Ann Arbor, MI
Kohei Maeda, University of Michigan, Ann Arbor, MI
Sharon E. Fox, LSU Health Sciences Center - New OrleansFollow
William D. Brodie, University of Michigan, Ann Arbor, MI
Megan N. Mattichak, University of Michigan, Ann Arbor, MI
Caroline Foster, University of Michigan, Ann Arbor, MI
Ajay Tambralli, University of Michigan, Ann Arbor, MI
Srilakshmi Yalavarthi, University of Michigan, Ann Arbor, MI
M Asif Amin, University of Michigan, Ann Arbor, MI
Katarina Kmetova, University of Michigan, Ann Arbor, MI
Bruna Mazetto Fonseca, University of Michigan, Ann Arbor, MI
Emily Chong, University of Michigan, Ann Arbor, MI
Yu Zuo, University of Michigan, Ann Arbor, MI
Michael D. Maile, University of Michigan, Ann Arbor, MI
Luisa Imberti, University of Brescia, Brescia, Italy
Arnaldo Caruso, University of Brescia, Brescia, Italy
Francesca Caccuri, University of Brescia, Brescia, Italy
Virginia Quaresima, ASST Spedali Civili of Brescia, Brescia, Italy
Alessandra Sottini, ASST Spedali Civili of Brescia, Brescia, Italy
Douglas B. Kuhns, Frederick National Laboratory for Cancer Research, Frederick, MD
et al

Document Type

Article

Publication Date

4-1-2025

Publication Title

JCI Insight

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 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.

PubMed ID

40168094

Volume

10

Issue

9

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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