Human and mouse neutrophils share core transcriptional programs in both homeostatic and inflamed contexts

Nicolaj S. Hackert, Felix A. Radtke, Tarik Exner, Hanns-Martin Lorenz, Carsten Müller-Tidow, Peter A. Nigrovic, Guido Wabnitz and Ricardo Grieshaber-Bouyer ()
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Nicolaj S. Hackert: Heidelberg University Hospital
Felix A. Radtke: Heidelberg University Hospital
Tarik Exner: Heidelberg University Hospital
Hanns-Martin Lorenz: Heidelberg University Hospital
Carsten Müller-Tidow: Heidelberg University Hospital
Peter A. Nigrovic: Harvard Medical School
Guido Wabnitz: Heidelberg University Hospital
Ricardo Grieshaber-Bouyer: Heidelberg University Hospital

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract Neutrophils are frequently studied in mouse models, but the extent to which findings translate to humans remains poorly defined. In an integrative analysis of 11 mouse and 13 human datasets, we find a strong correlation of neutrophil gene expression across species. In inflammation, neutrophils display substantial transcriptional diversity but share a core inflammation program. This program includes genes encoding IL-1 family members, CD14, IL-4R, CD69, and PD-L1. Chromatin accessibility of core inflammation genes increases in blood compared to bone marrow and further in tissue. Transcription factor enrichment analysis implicates members of the NF-κB family and AP-1 complex as important drivers, and HoxB8 neutrophils with JunB knockout show a reduced expression of core inflammation genes in resting and activated cells. In independent single-cell validation data, neutrophil activation by type I or type II interferon, G-CSF, and E. coli leads to upregulation in core inflammation genes. In COVID-19 patients, higher expression of core inflammation genes in neutrophils is associated with more severe disease. In vitro treatment with GM-CSF, LPS, and type II interferon induces surface protein upregulation of core inflammation members. Together, we demonstrate transcriptional conservation in neutrophils in homeostasis and identify a core inflammation program shared across heterogeneous inflammatory conditions.

Date: 2023
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DOI: 10.1038/s41467-023-43573-9

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