Journal article
CXCL12 ameliorates neutrophilia and disease severity in SARS-CoV-2 infection
The Journal of clinical investigation, Vol.135(4), e188222
02/17/2025
DOI: 10.1172/JCI188222
PMCID: PMC11827850
PMID: 39773555
Abstract
Neutrophils, particularly low-density neutrophils (LDNs), are believed to contribute to acute COVID-19 severity. Here, we showed that neutrophilia can be detected acutely and even months after SARS-CoV-2 infection in patients and mice, while neutrophil depletion reduced disease severity in mice. A key factor in neutrophilia and severe disease in infected mice was traced to the chemokine CXCL12 secreted by bone marrow cells and unexpectedly, endothelial cells. CXCL12 levels were negatively correlated with LDN numbers in longitudinal analyses of patient blood samples. CXCL12 blockade in SARS-CoV-2-infected mice increased blood/lung neutrophil numbers thereby accelerating disease progression without changing lung virus titers. The exaggerated mortality caused by CXCL12 blockade can be reversed by neutrophil depletion. In addition, blocking interactions between SARS-CoV-2 and Angiotensin-Converting Enzyme 2 (ACE2) reduced CXCL12 levels, suggesting a signal transduction from virus-mediated ACE2 ligation to increased CXCL12 secretion. Collectively, these results demonstrate a previously unappreciated role of CXCL12 in diminishing neutrophilia, including low density neutrophilia, and its deleterious effects in SARS-CoV-2 infections. The results also support the involvement of SARS-CoV-2-endothelial cell interactions in viral pathogenesis.
Details
- Title: Subtitle
- CXCL12 ameliorates neutrophilia and disease severity in SARS-CoV-2 infection
- Creators
- Jian Zheng - University of LouisvilleHima Dhakal - University of LouisvilleEnya Qing - Loyola University ChicagoRejeena Shrestha - University of LouisvilleAnne E Geller - University of LouisvilleSamantha M Morrissey - University of LouisvilleDivyasha Saxena - University of LouisvilleXiaoling Hu - University of LouisvilleHong Li - University of LouisvilleHaiyan Li - University of LouisvilleKevin Wilhelmsen - BioAgeLinder H Wendt - University of IowaKlaus Klumpp - BioAgePatrick S Hume - National Jewish HealthWilliam J Janssen - National Jewish HealthRachel Brody - Icahn School of Medicine at Mount SinaiKenneth E Palmer - University of LouisvilleSilvia M Uriarte - University of LouisvillePatrick P Ten Eyck - University of IowaDavid K Meyerholz - University of IowaMichael L Merchant - University of LouisvilleKenneth McLeish - University of LouisvilleTom Gallagher - Loyola University ChicagoJiapeng Huang - University of LouisvilleJun Yan - University of LouisvilleStanley Perlman - University of Iowa
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.135(4), e188222
- DOI
- 10.1172/JCI188222
- PMID
- 39773555
- PMCID
- PMC11827850
- NLM abbreviation
- J Clin Invest
- ISSN
- 1558-8238
- eISSN
- 1558-8238
- Publisher
- AMER SOC CLINICAL INVESTIGATION INC
- Grant note
- US NIH: P01 AI060699, R01 AI129269, R01 AI172873, R01 HL158779, P20 GM155899, 4U18TR003787, P30 ES030283, UM1TR004403 Universi-ty of Louisville: F1256, F1260, COBRE GB180729A5
Acknowledgments We thank William Nauseef for careful review of the manuscript. This work was supported in part by US NIH grants P01 AI060699 (to SP) , R01 AI129269 (to SP) , R01 AI172873 and R01 HL158779 (to JY, SU, JH) , P20 GM155899 (to JH) , 4U18TR003787 (to JH) , P30 ES030283 (to JH) . UM1TR004403 (to LHW, PTE) , Universi-ty of Louisville startup grants F1256, F1260 (to JZ) , and COBRE GB180729A5 (to JZ) .
- Language
- English
- Electronic publication date
- 01/07/2025
- Date published
- 02/17/2025
- Academic Unit
- Microbiology and Immunology; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Biostatistics; Infectious Disease (Pediatrics); Design Biostat and Ethics
- Record Identifier
- 9984771628902771
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