Neutrophil fate in bone infection: Mechanisms, microenvironment, and therapeutic opportunities
- 1Graduate School of Bengbu Medical University, Bengbu, China; Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- 2Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- 3Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Corresponding author.
Abstract
The clinical challenge of eradicating bone infection stems from microbial persistence within a distinct skeletal niche that is poorly perfused, hypoxic, mineralised, and highly susceptible to collateral damage. Neutrophils are central arbiters of this process and function as a double-edged sword: they are indispensable for initial pathogen containment, yet can become major drivers of chronic osteolysis, biofilm persistence, and inflammation when their effector programmes turn maladaptive. Recent high-resolution single-cell and spatial analyses have overturned the traditional view of neutrophils as short-lived, homogeneous cells, instead revealing a complex spectrum of functional states shaped by the infected bone microenvironment. In this Review, we use a neutrophil fate framework that distinguishes three related but non-equivalent levels: irreversible terminal fates, non-terminal tissue-disposition states and outcomes, and upstream fate-biasing states or processes. Terminal fates include apoptosis with subsequent efferocytic clearance, suicidal NETosis, pyroptosis, necroptosis, ferroptosis, mitochondrial permeability transition-driven necrosis, and secondary necrosis. By contrast, non-lytic (vital) NET release is considered an effector process rather than a terminal fate. Reverse migration is treated as a non-terminal tissue-exit outcome, whereas inflammatory retention is considered a non-terminal persistence state. Upstream fate-biasing factors include phenotypic or activation states, such as cellular ageing, NET-prone activation, and apoptosis delay, as well as regulatory processes including autophagy and metabolic or redox stress; none of these is classified as an independent terminal fate. We further examine how these terminal fates, non-terminal tissue-disposition states and outcomes, and upstream fate-biasing states and processes are spatially organised across osteomyelitic lesions and biofilm-associated interfaces, and how they govern interactions with osteoblasts, osteoclasts, and macrophages to determine the balance between antimicrobial control and progressive skeletal destruction. We also discuss emerging therapeutic paradigms aimed not at broadly suppressing neutrophil recruitment, but at precisely redirecting neutrophil fate, thereby providing a conceptual basis for stage-specific immunomodulation in orthopaedic infection. The Translational Potential of this Article This Review provides a fate-based framework for understanding how neutrophils shape the balance between pathogen control, biofilm persistence, osteolysis, and tissue repair in orthopaedic infection. By linking neutrophil fate programmes to distinct lesion microenvironments, including osteomyelitic lesions, implant-associated biofilms, contiguous soft-tissue infection, and fracture-related infection, this article highlights potential translational opportunities for stage- and compartment-specific immune modulation. These include improving patient stratification, guiding the timing of surgical source control and implant retention or removal, optimising dead-space management and local antimicrobial delivery, supporting vascularised soft-tissue reconstruction, and developing biomarkers that distinguish protective antimicrobial neutrophil responses from destructive inflammatory persistence. This framework may help shift future orthopaedic infection management from nonspecific suppression of inflammation toward precision redirection of maladaptive neutrophil fate while preserving early host defence and tissue repair capacity.
Related
- Tumor microenvironment-driven immune evasion in triple-negative breast cancer: mechanisms, clinical challenges, and therapeutic opportunities
- Neutrophil Extracellular Traps at the Asthma + COPD Interface: Mechanisms, Experimental Models, and Therapeutic Targeting
- Stem cell factor in allergic diseases: mechanisms of type 2 immunity and therapeutic opportunities
- Neutrophils and Neutrophil Extracellular Traps in Cancer and Cardio-Oncology: Molecular Mechanisms, Therapeutic Targeting, and Clinical Perspectives.
- Itaconate as an immunometabolic hub in host-pathogen interactions: Mechanisms, resistance, and therapeutic opportunities.
BibTeX
@article{cai2026neutrophil,
title = {{Neutrophil fate in bone infection: Mechanisms, microenvironment, and therapeutic opportunities}},
author = {Chenguang Cai and Yu Ji and Jiawei Mei and Zhengxi Wang and Quan Liu and Wangyang Fan and Yiming Zhao and Xiang Chen and Chen Zhu and Wanbo Zhu and Qianming Li},
journal = {Journal of Orthopaedic Translation},
year = {2026},
month = oct,
doi = {10.1016/j.jot.2026.101232},
url = {https://doi.org/10.1016/j.jot.2026.101232},
note = {CC BY},
}
RIS
TY - JOUR
TI - Neutrophil fate in bone infection: Mechanisms, microenvironment, and therapeutic opportunities
AU - Chenguang Cai
AU - Yu Ji
AU - Jiawei Mei
AU - Zhengxi Wang
AU - Quan Liu
AU - Wangyang Fan
AU - Yiming Zhao
AU - Xiang Chen
AU - Chen Zhu
AU - Wanbo Zhu
AU - Qianming Li
PY - 2026
DA - 2026/10/24
JO - Journal of Orthopaedic Translation
DO - 10.1016/j.jot.2026.101232
UR - https://doi.org/10.1016/j.jot.2026.101232
AB - The clinical challenge of eradicating bone infection stems from microbial persistence within a distinct skeletal niche that is poorly perfused, hypoxic, mineralised, and highly susceptible to collateral damage. Neutrophils are central arbiters of this process and function as a double-edged sword: they are indispensable for initial pathogen containment, yet can become major drivers of chronic osteolysis, biofilm persistence, and inflammation when their effector programmes turn maladaptive. Recent high-resolution single-cell and spatial analyses have overturned the traditional view of neutrophils as short-lived, homogeneous cells, instead revealing a complex spectrum of functional states shaped by the infected bone microenvironment. In this Review, we use a neutrophil fate framework that distinguishes three related but non-equivalent levels: irreversible terminal fates, non-terminal tissue-disposition states and outcomes, and upstream fate-biasing states or processes. Terminal fates include apoptosis with subsequent efferocytic clearance, suicidal NETosis, pyroptosis, necroptosis, ferroptosis, mitochondrial permeability transition-driven necrosis, and secondary necrosis. By contrast, non-lytic (vital) NET release is considered an effector process rather than a terminal fate. Reverse migration is treated as a non-terminal tissue-exit outcome, whereas inflammatory retention is considered a non-terminal persistence state. Upstream fate-biasing factors include phenotypic or activation states, such as cellular ageing, NET-prone activation, and apoptosis delay, as well as regulatory processes including autophagy and metabolic or redox stress; none of these is classified as an independent terminal fate. We further examine how these terminal fates, non-terminal tissue-disposition states and outcomes, and upstream fate-biasing states and processes are spatially organised across osteomyelitic lesions and biofilm-associated interfaces, and how they govern interactions with osteoblasts, osteoclasts, and macrophages to determine the balance between antimicrobial control and progressive skeletal destruction. We also discuss emerging therapeutic paradigms aimed not at broadly suppressing neutrophil recruitment, but at precisely redirecting neutrophil fate, thereby providing a conceptual basis for stage-specific immunomodulation in orthopaedic infection. The Translational Potential of this Article This Review provides a fate-based framework for understanding how neutrophils shape the balance between pathogen control, biofilm persistence, osteolysis, and tissue repair in orthopaedic infection. By linking neutrophil fate programmes to distinct lesion microenvironments, including osteomyelitic lesions, implant-associated biofilms, contiguous soft-tissue infection, and fracture-related infection, this article highlights potential translational opportunities for stage- and compartment-specific immune modulation. These include improving patient stratification, guiding the timing of surgical source control and implant retention or removal, optimising dead-space management and local antimicrobial delivery, supporting vascularised soft-tissue reconstruction, and developing biomarkers that distinguish protective antimicrobial neutrophil responses from destructive inflammatory persistence. This framework may help shift future orthopaedic infection management from nonspecific suppression of inflammation toward precision redirection of maladaptive neutrophil fate while preserving early host defence and tissue repair capacity.
SN - 2214-031X
SN - 2214-0328
ER -