Multi‑omics reveal neutrophil heterogeneity in sepsis (Review)

Abstract

Sepsis is a life‑threatening disease characterized by a dysregulated immune response, and neutrophils serve an important role in pathogen clearance, multiple organ failure and immune regulation. With the discovery of multiple phenotypical and functional variants of neutrophils in sepsis, the heterogeneity of neutrophils is crucial, as it impacts the effectiveness of the immune response and the overall outcome of sepsis. Various genome, transcriptome, proteome and metabolome properties may contribute to this heterogeneity. Multi‑omics approaches unveil complex details of neutrophil behavior in the context of sepsis, highlighting how neutrophil phenotypes are differentially recruited and activated in response to various stimuli. The present review aimed to provide an overview of the differences in neutrophil phenotypes and functions during sepsis, focusing on neutrophil heterogeneity identified via multi‑omics methods. Comprehensive understanding of multi‑omics data regarding neutrophil heterogeneity enhances the diagnostic accuracy of sepsis and provides a scientific basis for individualized treatment strategies, potentially improving patient outcomes by targeting specific neutrophil functions and states.

Keywords: heterogeneity; multi‑omics; neutrophil; sepsis.

Figure 1

Phenotypical heterogeneity of neutrophils in homeostasis and sepsis. Under homeostatic conditions, immature neutrophils are characterized by expression of CD64, CD49d and CXCR4, whereas mature neutrophils typically express CD10, CD16b and CD35. During sepsis, both immature and mature neutrophils are exposed to inflammatory cues that reprogram cellular activities and functional states, leading to marked phenotypical shifts. Specifically, surface molecules such as CD11b, CD64, CD177, ICAM-1 and TREM-1 are upregulated, while CD10, CD62L, CD16 and CXCR2 are downregulated. These alterations reflect changes in neutrophil activation, adhesion and migration, however, the precise functional consequences and regulatory mechanisms underlying these transitions remain incompletely understood. CXCR, C-X-C chemokine receptor; ICAM-1, intercellular adhesion molecule-1; TREM-1, triggering receptor expressed on myeloid cells-1.

Figure 2

Multi-omics approaches reveal neutrophil heterogeneity and clinical implications in sepsis. Omics layers include genome, transcriptome, proteome, metabolome and microbiome. Neutrophil subsets and characteristics are identified through single-omics studies and multi-omics integration in sepsis. Potential clinical applications of neutrophil heterogeneity profiling include early detection, patient stratification, targeted therapy, prognostic modeling and precision medicine. eQTL, expression quantitative trait loci; MPO, myeloperoxidase; H3K4me3, histone H3 lysine 4 trimethylation; PI3K/AKT, phosphatidylinositol 3-kinase/protein kinase B; PD-L1, programmed death-ligand 1; MKI67, marker of proliferation Ki-67; CYP1B1, cytochrome P450 family 1 subfamily B member 1; CEACAM8, carcinoembryonic antigen-related cell adhesion molecule 8; S100A8/9, S100 calcium-binding protein A8/9; LDHA, lactate dehydrogenase A; Neu1, neutrophil subtype 1.