Neutrophil heterogeneity and emergence of a distinct population of CD11b/CD18-activated low-density neutrophils after trauma
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Updated: Aug 12, 2025
Isolation and Characterization of Neutrophils with Anti-Tumor Properties
Published on: June 19, 2015
Ingred Goretti Riça1, Brian A Joughin, Martha E Teke
1From the Departments of Biological Engineering and Biology (I.G.R., B.A.J., T.R.E., M.B.Y.), Massachusetts Institute of Technology, Cambridge, Massachusetts; Koch Institute for Integrative Cancer Research (I.G.R., B.A.J., T.R.E., M.B.Y.), Massachusetts Institute of Technology, Cambridge, Massachusetts; Center for Precision Cancer Medicine (I.G.R., B.A.J., T.R.E., M.B.Y.), Massachusetts Institute of Technology, Cambridge, Massachusetts; Surgical Oncology Program (M.E.T., J.M.H., M.B.Y.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland; Department of Surgery (A.M.G., L.A.C., J.A.L.), Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Department of Anesthesia, Critical Care, and Pain Medicine (V.M.B.-G., S.C.R.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; Department of Medicine (B.H.S.), Roswell Park Comprehensive Cancer Center, University of Buffalo School of Medicine, Buffalo, New York; and Department of Surgery (L.E.O., C.J.H., M.B.Y.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
Introduction:
Multiple large clinical trauma trials have documented an increased susceptibility to infection after injury. Although neutrophils (polymorphonuclear leukocytes [PMNs]) were historically considered a homogeneous cell type, we hypothesized that injury could alter neutrophil heterogeneity and predispose to dysfunction. To explore whether trauma modifies PMN heterogeneity, we performed an observational mass-spectrometry-based cytometry study on total leukocytes and low-density PMNs found in the peripheral blood mononuclear cell fraction of leukocytes from healthy controls and trauma patients.
Methods:
A total of 74 samples from 12 trauma patients, each sampled at 1 or more time points, and matched controls were fractionated and profiled by mass-spectrometry-based cytometry using a panel of 44 distinct markers. After deconvolution and conservative gating on neutrophils, data were analyzed using Seurat, followed by clustering of principal components.
Results:
Eleven distinct neutrophil populations were resolved in control and trauma neutrophils based on differential protein surface marker expression. Trauma markedly altered the basal heterogeneity of neutrophil subgroups seen in the control samples, with loss of a dominant population of resting neutrophils marked by high expression of C3AR and low levels of CD63, CD64, and CD177 (cluster 1), and expansion of two alternative neutrophil populations, one of which is marked by high expression of CD177 with suppression of CD10, CD16, C3AR, CD63, and CD64 (cluster 6). Remarkably, following trauma, a substantially larger percentage of neutrophils sediment in the monocyte fraction. These low-density neutrophils bear markers of functional exhaustion and form a unique trauma-induced population (cluster 9) with markedly upregulated expression of active surface adhesion molecules (activated CD11b/CD18), with suppression of nearly all other surface markers, including receptors for formyl peptides, leukotrienes, chemokines, and complement.
Conclusion:
Circulating neutrophils demonstrate considerable evidence of functional heterogeneity that is markedly altered by trauma. Trauma induces evolution of a novel, exhausted, low-density neutrophil population with immunosuppressive features.
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