Single-Cell Atlas of Human Neutrophils Reveals Heterogeneity Across Health and Disease

A million-cell atlas mapping human neutrophils across 43 datasets has revealed that these immune cells form distinct transcriptional states varying by tissue, infection, cancer, sex, and metabolic health. The Single-Cell Atlas of Human Neutrophils, or SCAHN, integrates data from 781 samples spanning nine countries, seven sequencing platforms, and more than 20 tissues and conditions, providing researchers with a reference tool to decode how seemingly identical blood cells drive different disease pathways.

Key Clinical Takeaways:

• The SCAHN atlas combines one million neutrophils from 781 samples across 40 studies to chart how immune states shift across diverse diseases.
• Higher neutrophil signature scores correlate with increased mortality risk in severe infections and specific cancer types.
• Analysis of over 200,000 patient records links elevated neutrophil counts to a higher risk of developing chronic conditions over time.

Mapping Neutrophil Heterogeneity Across Tissues and Conditions

The research team integrated single-cell RNA sequencing data with 17,023 bulk blood transcriptome profiles from 40 datasets and two large electronic health record databases. Published in Nature Immunology, the retrospective computational reanalysis describes biological patterns and associations that still require prospective validation. The atlas resolves broad developmental compartments before identifying finer states, showing that mature neutrophils express high levels of FCGR3B, CXCR1, CXCR2, and MME, while immature neutrophils express CEACAM8 and other granule genes.

The analysis identified specific immune programs within these cells. Three subsets expressed type I interferon genes, type II interferon genes, or both, while six subsets were named for prominent cytokine or inflammatory genes such as CXCL, CCL3/4, NF-kappa B, IL1B, IL1RN, and VEGFA. These cytokine and inflammation states proved significantly more abundant in solid tissues than in whole blood or purified blood neutrophils.

Infection and Cancer Outcomes Linked to Specific Cellular Signatures

To enable the atlas’s application in standard blood studies, the researchers established five distinct neutrophil gene signatures that encompass the mature, total neutrophil, degranulating, antiprotease, and immature compartments. A separate signature summarized interferon-related genes. Looking at 167 samples drawn from seven infectious-disease datasets, subsets corresponding to AZU1, LTF, and MMP9 appeared at higher levels among individuals with bacterial sepsis or severe COVID-19 than in healthy or convalescent subjects. Evaluating 3,381 individuals sourced from critical-illness or infection databases, elevated scores for total, degranulating, and immature neutrophil signatures correlated with an increased likelihood of 28- or 30-day mortality after controlling for sex and age.

In cancer analyses encompassing 131 samples from six single-cell studies, four inflammatory subsets—VEGFA, CCL3/4, NF-kappa B, and IL1RN—appeared more abundant in pretreatment tumors than in adjacent tissue. In an analysis of the randomized SAVE-MORE trial, anakinra, an interleukin-1 blocker, associated with lower 28- or 30-day mortality in patients with low baseline IL1B expression, though this finding stemmed from a retrospective median-based subgroup analysis rather than a prospectively stratified trial.

Lifestyle Factors and Glucose Levels Shape Neutrophil Signatures

Demographic and lifestyle factors also shaped these signatures. Among 33 healthy single-cell donors, females exhibited a higher proportion of the combined type I and type II interferon subset, whereas males showed higher CCL3/4 and CXCL subsets. Within Framingham Heart Study records covering 5,321 participants, metrics for glucose, glycated hemoglobin, and triglycerides demonstrated direct correlations with every neutrophil-specific score except the mature score, whereas high-density lipoprotein cholesterol showed inverse associations with them.

Retrospective health-record analyses extended these gene expression findings to routine blood counts. Among 205,817 Stanford patients with normal absolute neutrophil counts and no Charlson-index comorbidities, patients presenting in the top quartile of cell counts experienced a heightened risk for subsequent chronic disease development, resulting in a 1.18 hazard ratio. The highest-count group also exhibited lower 10-year survival, with a hazard ratio of 1.98. When the findings were replicated using data from 224,771 Arcadia patients, a comparable link to chronic illness emerged, showing a hazard ratio of 1.27 when comparing the highest count quartile against the lowest.

Disclaimer: The information provided in this article is for educational and scientific communication purposes only and does not constitute medical advice. Always consult with a qualified healthcare provider regarding any medical condition, diagnosis, or treatment plan.