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 1

Neutrophilia and accumulated LDNs in COVID-19 patients.

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Neutrophilia and accumulated LDNs in COVID-19 patients. (A) Massive infi...
(A) Massive infiltration of LDNs in the lungs of deceased COVID-19 patients was identified with metal isotope–labeled antibodies (left and right panels). Images are representative of 5 slides from 5 deceased COVID-19 cases. Scale bars: 100 μm. The percentage of CD16hi and CD16int neutrophils in 3 regions of interest (ROIs) of each slide (middle panel) was quantitated by FlowJo after converting imaging files into fcs files. ****P < 0.0001 by Student’s t test. (B) Peripheral blood LDNs in healthy donors (HD, n = 13) and COVID-19 patients with moderate (n = 23) or severe disease (n = 16). **P < 0.01; ****P < 0.0001 by 1-way ANOVA with Tukey’s multiple comparisons. (C–E) A cohort of convalescent COVID-19 patients and healthy donors were recruited at times ranging from 1 month to 13 months after hospital discharge. A representative flow plot (C) and summary (D) of CD66b+ LDN frequency in the peripheral blood of convalescent patients (CP, collected at 1–13 months after discharge) and age-matched healthy donors (HD) are shown. n = 11. *P < 0.05 by Student’s t test. (E) Frequency of LDNs was negatively correlated with time from discharge (each point represents the data obtained from an individual patient). (F and G) A total of 1830 proteins were identified by mass spectrometry of normal-density neutrophils (NDNs) and low-density neutrophils (LDNs) analyzed from each of 13 patients with severe COVID-19. Proteins were quantified from average peptide expression of pooled data using Scaffold, and differential expression of proteins was determined by analysis with MetaboAnalyst. (F) A volcano plot of the 1830 proteins expressed by NDNs and LDNs from COVID-19 patients, comparing log2(fold change) to –log10(P value), with proteins above the red line demonstrating P < 0.05. A total of 326 proteins showed significantly greater expression in NDNs, and 134 proteins showed significantly greater expression in LDNs. (G) Differences in the pattern of protein expression by LDNs and NDNs were compared using orthogonal partial least squares discriminant analysis (orthoPLS-DA).