CXCL12 ameliorates neutrophilia and disease severity in SARS-CoV-2 infection
Jian Zheng, … , Jun Yan, Stanley Perlman
Jian Zheng, … , Jun Yan, Stanley Perlman
Published January 7, 2025
Citation Information: J Clin Invest. 2025;135(4):e188222. https://doi.org/10.1172/JCI188222.
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Research Article Infectious disease

CXCL12 ameliorates neutrophilia and disease severity in SARS-CoV-2 infection

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 could 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.

Authors

Jian Zheng, Hima Dhakal, Enya Qing, Rejeena Shrestha, Anne E. Geller, Samantha M. Morrissey, Divyasha Saxena, Xiaoling Hu, Hong Li, Haiyan Li, Kevin Wilhelmsen, Linder H. Wendt, Klaus Klumpp, Patrick S. Hume, William J. Janssen, Rachel Brody, Kenneth E. Palmer, Silvia M. Uriarte, Patrick Ten Eyck, David K. Meyerholz, Michael L. Merchant, Kenneth McLeish, Tom Gallagher, Jiapeng Huang, Jun Yan, Stanley Perlman

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Figure 4

Accumulation of LDNs correlates with disease severity of SARS2-N501YMA30–infected mice.

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Accumulation of LDNs correlates with disease severity of SARS2-N501YMA30...
(A) The percentage and absolute number of peripheral blood neutrophil subsets — CD15+CD16+CD115–CXCR2– (immature), CD16hiCD62LhiCXCR2hiCXCR4lo (mature), CD11bhi CXCR2loCD62LloCXCR4hi (senescent), CD11b+CD18+Gr-1int (degranulated), and ARG1+CD15+CD33+CD101–CXCR4+ (LDNs) — in SARS2-N501YMA30–infected mice on day 5 after infection (n = 5). Data are mean ± SEM and are representative of 3 independent experiments. *P < 0.05, **P < 0.01 by Student’s t test. (B and C) Correlation between fold increase in peripheral blood (B) and lung (C) immature neutrophils, degranulated neutrophils, and LDNs, and weight change of SARS2-N501YMA30–infected mice on day 5 after infection (n = 8). Peripheral blood: R = 0.3744 (P = 0.1069), 0.06653 (P = 0.5374), and 0.6501 (P = 0.0156) for immature neutrophils, degranulated neutrophils, and LDNs. Lung: R =0.2862 (P = 0.1719), 0.01357 (P = 0.7836), and 0.9016 (P = 0.0003) for immature neutrophils, degranulated neutrophils, and LDNs. Data are representative of 2 independent experiments. (D and E) Young (8- to 10-week-old) or middle-aged (8- to 10-month-old) C57BL/6N mice were sublethally infected with 1000 or 2000 PFU. The numbers of peripheral blood neutrophils (D) and LDNs (E) were determined at the indicated time points by flow cytometry. n = 5. Data are mean ± SEM and are representative of 2 independent experiments. *P < 0.05; **P < 0.01 by 1-way ANOVA with Tukey’s multiple comparisons.