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

TitleSoluble CD13 is a potential mediator of neutrophil-induced thrombogenic inflammation in SARS-CoV-2 infection.
Publication TypeJournal Article
Year of Publication2025
AuthorsTsou P-S, Ali RA, Lu C, Sule G, Carmona-Rivera C, Lucotti S, Ikari Y, Wu Q, Campbell PL, Gurrea-Rubio M, Maeda K, Fox SE, Brodie WD, Mattichak MN, Foster C, Tambralli A, Yalavarthi S, M Amin A, Kmetova K, Fonseca BMazetto, Chong E, Zuo Y, Maile MD, Imberti L, Caruso A, Caccuri F, Quaresima V, Sottini A, Kuhns DB, Fink D, Castagnoli R, Delmonte OM, Kenney H, Zhang Y, Magliocco M, Su H, Notarangelo L, Zemans RL, Mao-Draayer Y, Matei IR, Salvatore M, Lyden D, Kanthi Y, Kaplan MJ, Knight JS, Fox DA
JournalJCI Insight
Volume10
Issue9
Date Published2025 May 08
ISSN2379-3708
KeywordsAdult, Aged, CD13 Antigens, COVID-19, Extracellular Traps, Female, Humans, Inflammation, Lung, Male, Middle Aged, Neutrophils, SARS-CoV-2, Thromboinflammation
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.

DOI10.1172/jci.insight.184975
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https://www.ncbi.nlm.nih.gov/pubmed/40168094?dopt=Abstract

Alternate JournalJCI Insight
PubMed ID40168094

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