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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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 3

Neutrophil depletion ameliorates disease severity of SARS2-N501YMA30–infected mice.

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Neutrophil depletion ameliorates disease severity of SARS2-N501YMA30–inf...
(A–C) Eight- to 10-month-old (n = 5) C57BL/6N mice were infected with 1000, 2000, or 5000 PFU SARS2-N501YMA30. Weight (A), survival (B), and lung infectious virus titers (C) are shown. Data are representative of 3 independent experiments. Data in A and C are mean ± SEM. LOD, limit of detection. u.d., undetected. *P < 0.05 by 1-way ANOVA with Tukey’s multiple comparisons in C. (D–H) Middle-aged C57BL/6N mice (8–10 months old, n = 5) were infected with 1000, 2000, or 5000 PFU SARS2-N501YMA30 virus. (D and F) The number of neutrophils in peripheral blood (D) and lung (F) of infected (n = 8) and control mice (n = 5) was determined by flow cytometry at the indicated time points. Data are mean ± SEM and are representative of 3 independent experiments. (E and G) The correlation between the fold increase in peripheral blood (E) or lung-derived (G) neutrophils and weight change of SARS2-N501YMA30–infected mice (n = 8) on day 5 after infection is shown. Data are representative of 3 independent experiments. (H) Infiltration of neutrophils (arrows) in lungs of mock- or SARS2-N501YMA30–infected (5000 PFU) mice. Images are representative of 3 independent experiments. Arrows: PMNs. (I–M) Eight- to 10-month-old C57BL/6N mice were infected with 5000 PFU SARS2-N501YMA30 and treated with PBS, α-Ly6G antibody, or isotype control (IC, isotype Ig) (n = 15 mice/group). Experimental setup (I), weight (J), survival (K), lung histopathology (L), and infectious virus titers (M) are shown. Data in J and M are mean ± SEM. Data in K are a summary of 3 independent experiments. Data in L are representative images and a summary of 2 independent experiments (data are mean ± SEM) (n = 9). **P < 0.01 by Student’s t-test. Scale bars: 25 μm (H) and 430 μm (L).