Evidence map›Paper›PMID 40168094›Full record

ArticleJCI insight2025

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

Pei-Suen Tsou, Ramadan A Ali, Chenyang Lu, Gautam Sule, Carmelo Carmona-Rivera, Serena Lucotti, Yuzo Ikari, Qi Wu, Phillip L Campbell, Mikel Gurrea-Rubio and 36 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in JCI insight, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

5 citing papers in PubMed.

  1. Article
  2. Article
  3. Article
  4. Review
  5. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

46 authors.

Pei-Suen TsouDivision of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA.
Ramadan A AliDivision of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA.
Chenyang LuDivision of Rheumatology, Department of Internal Medicine, the Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Gautam SuleDivision of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA.
Carmelo Carmona-RiveraSystemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland, USA.
Serena LucottiDepartment of Pediatrics, Weill Cornell Medical College, New York, New York, USA.
Yuzo IkariDivision of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA.
Qi WuDivision of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA.
Phillip L CampbellDivision of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA.
Mikel Gurrea-RubioDivision of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA.
Kohei MaedaDivision of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA.
Sharon E FoxDepartment of Pathology, Louisiana State University, Health Sciences Center, New Orleans, Louisiana, USA.
William D BrodieDivision of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA.
Megan N MattichakDivision of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA.
Caroline FosterDivision of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA.
Ajay TambralliDivision of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA.
Srilakshmi YalavarthiDivision of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA.
M Asif AminDivision of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA.
Katarina KmetovaDivision of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA.
Bruna Mazetto FonsecaDivision of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA.
Emily ChongDivision of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA.
Yu ZuoDivision of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA.
Michael D MaileDepartment of Anesthesiology, University of Michigan, Ann Arbor, Michigan, USA.
Luisa ImbertiSection of Microbiology, University of Brescia, Brescia, Italy.
Arnaldo CarusoSection of Microbiology, University of Brescia, Brescia, Italy.
Francesca CaccuriSection of Microbiology, University of Brescia, Brescia, Italy.
Virginia QuaresimaClinical Chemistry Laboratory, ASST Spedali Civili of Brescia, Brescia, Italy.
Alessandra SottiniClinical Chemistry Laboratory, ASST Spedali Civili of Brescia, Brescia, Italy.
Douglas B KuhnsLeidos Biomedical Research, Inc.; Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
Danielle FinkLeidos Biomedical Research, Inc.; Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
Riccardo CastagnoliDivision of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
Ottavia M DelmonteDivision of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
Heather KenneyDivision of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
Yu ZhangDivision of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
Mary MaglioccoDivision of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
Helen SuDivision of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
Luigi NotarangeloDivision of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
Rachel L ZemansDivision of Pulmonary & Critical Care Medicine, Department of Internal Medicine; and Program in Cellular and Molecular Biology, School of Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Yang Mao-DraayerMultiple Sclerosis Center of Excellence, Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA.
Irina R MateiDepartment of Pediatrics, Weill Cornell Medical College, New York, New York, USA.
Mirella SalvatoreJoan and Sanford I. Weill Department of Medicine and Department of Population Health Sciences, Weill Cornell Medical College, New York, New York, USA.
David LydenDepartment of Pediatrics, Weill Cornell Medical College, New York, New York, USA.
Yogendra KanthiDivision of Intramural Research, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
Mariana J KaplanSystemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland, USA.
Jason S KnightDivision of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA.
David A FoxDivision of Rheumatology, Department of Internal Medicine, and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, Michigan, USA.

Funding

Systemic AutoimmunityZIAAR041199 · NIAMS · NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES · PI KAPLAN, MARIANA · 2014 to 2025
$32.5M
Host factors contributing to susceptibility to COVID-19 diseaseZIAAI001265 · NIAID · NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES · PI SU, HELEN CHUN-HUI · 2020 to 2025
$9.5M
Purinergic modulation of the autoimmune vascular phenotypeR01HL134846 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Jason Knight · 2018 to 2026
$4.8M
Mechanisms of Alveolar Homeostasis, Injury, Regeneration, and FibrosisR35HL160770 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Rachel Lynne Zemans · 2022 to 2026
$4.3M
Role of the Hippo pathway in scleroderma pathogenesisR01AI183620 · NIAID · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Johann Eli Gudjonsson, DINESH KHANNA · 2024 to 2026
$1.8M
Characterization of host immune responses to SARS-CoV-2ZIAAI001270 · NIAID · NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES · PI NOTARANGELO, LUIGI · 2020 to 2025
$1.2M
University of Michigan Clinical Autoimmunity Center of ExcellenceUM1AI144298 · NIAID · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI FOX, DAVID ALAN, KHANNA, DINESH · 2019 to 2023
$546k
Roles of soluble CD13 and its receptor in angiogenesis, monocyte recruitment, and joint inflammationR56AR076384 · NIAMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI FOX, DAVID ALAN · 2020 to 2020
$447k
Intramural NIH HHS ZIA AI001265Intramural NIH HHS ZIA AI001270Intramural NIH HHS ZIA AR041199NHLBI NIH HHS R01 HL134846NHLBI NIH HHS R35 HL160770NIAID NIH HHS R01 AI183620NIAID NIH HHS UM1 AI144298NIAMS NIH HHS R56 AR076384
6 · The paper itself

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.

Indexed as

CD13 AntigensCOVID-19NeutrophilsThromboinflammationAdultAgedExtracellular TrapsFemaleHumansInflammationLungMaleMiddle AgedSARS-CoV-2CD13 AntigensCOVID-19Endothelial cellsImmunologyInfectious diseaseNeutrophilsThrombosis

Identifiers

PMID40168094
PMCPMC12128962

What Socratic holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.