Sepsis remains a life-threatening syndrome defined by immune dysregulation and organ dysfunction. While neutrophils act as the primary defenders of the innate immune system, their rapid production during sepsis, a process known as emergency granulopoiesis (EG), often creates a paradoxical effect. This response typically leads to a "left shift," marked by an elevated number of immature neutrophils in the blood. Despite their abundance, these cells frequently fail to clear pathogens effectively. Instead, they often exacerbate tissue damage and contribute to immune paralysis. Understanding why this compensatory mechanism turns maladaptive is therefore essential for the development of precise therapeutic interventions.
In a comprehensive review published in Research, investigators from Zhongda Hospital, School of Medicine, Southeast University propose an integrative framework centered on EG to explain this shift from defense to dysfunction. The authors synthesize evidence across single-cell multi-omics, bone-marrow niche remodeling, and immunometabolic reprogramming. By integrating single-cell biology with bedside indicators, this work clarifies why a protective program becomes maladaptive and outlines practical avenues for biomarker-guided stratification.
The lead authors are Prof. Xiaojing Wu, Prof. Yingzi Huang and Prof. Haibo Qiu from Zhongda Hospital, School of Medicine, Southeast University.

Quantity Over Quality: A Metabolic Trade-off
Under normal homeostatic conditions, neutrophil maturation is a strictly regulated process that takes approximately 10 days. However, sepsis-induced EG forces the bone marrow to compress this cycle to a mere 48 to 72 hours. This acceleration represents a compromise that prioritizes quantity over quality, driven by inflammatory signals such as G-CSF and IL-6. The review details how this process relies on a distinct transcriptional shift. Unlike the steady-state reliance on C/EBPα, EG is governed by C/EBPβ and STAT3. These factors prioritize rapid progenitor proliferation rather than functional maturation. As a result, the bone marrow releases distinct immature neutrophil subsets with abnormal features, including reduced CD10 and CD16 expression as well as atypical nuclear morphology.

Mechanisms of Dysfunction: Paralysis and Suppression
The researchers synthesized evidence showing that these immature neutrophils act as pathological effectors and are not simply developmentally arrested cells. They exhibit "neutrophil paralysis," a condition characterized by defective chemotaxis to infection sites. Instead of fighting infection, they accumulate in the microvasculature of organs like the lungs and liver, which contributes to Multiple Organ Dysfunction Syndrome (MODS). In terms of function, their phagocytic efficiency against bacteria drops by approximately 40%. Yet, these cells generate excessive reactive oxygen species (ROS) and neutrophil extracellular traps (NETs), which exacerbates oxidative tissue injury and coagulopathy. Furthermore, specific subsets, particularly CD10⁻CD16low neutrophils, express high levels of PD-L1 and Arginase-1. These cells potently inhibit T-cell proliferation and drive the host into a state of late-stage immunoparalysis.

Systemic Remodeling and Future Therapies
EG also reshapes the broader immune landscape. The expansion of the myeloid lineage occurs at the expense of lymphopoiesis and erythropoiesis, leading to lymphopenia and anemia. The authors highlight that the "Immature-to-Total neutrophil ratio" (I/T ratio) serves as a critical biomarker that correlates with disease severity." Future therapeutic strategies must shift from broad immunosuppression to precision interventions," the team suggests. Promising approaches include the use of CXCR2 antagonists to prevent premature egress or the modulation of metabolic pathways to restore neutrophil fitness. However, the authors caution that interventions such as GM-CSF inhibition require careful timing based on the patient's immune endotype to avoid worsening immunoparalysis.

The complete study is accessible via DOI:10.34133/research.1011