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Published on: June 24, 2025
FKBP5 Orchestrates a Biphasic Microglial Response in Spinal Cord Injury by Sequentially Activating the GPR84/IL-1β
Haotian Li1, Jing Wang2, Daohui Li1
1Department of Orthopaedics, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China.
Abstract:
Spinal cord injury often causes permanent disability because the body's own repair mechanisms are limited, and the molecules that control damage and healing are not fully understood. One such molecule, FK506-binding protein 5 (FKBP5), is known to rise sharply after injury, but whether it only drives harmful inflammation or also participates in later recovery has been unclear. In this study, we investigated how FKBP5 affects microglia-the brain's immune cells-at different stages after spinal cord injury in mice. We found that FKBP5 plays a dual role. In the first few days, it works together with another protein, GPR84, to boost the production of an inflammatory signal called interleukin-1β. This signal pushes microglia into a destructive state and triggers a coordinated form of neuronal cell death that involves multiple death pathways. However, as FKBP5 levels continue to rise over time, it switches its function. It binds to and modifies an enzyme called LDHA, changing how microglia process lactate. This lactate then acts as a signal to add chemical tags (lactylation) onto histones, which turns on a protective gene, Fxyd5, and its partner Lgals1. These changes convert microglia from a harmful to a healing state, reduce neuronal death, and improve the local environment for tissue repair. Our results reveal that FKBP5 is a double-edged sword-first worsening damage, then promoting repair. This discovery suggests that precisely timing therapies that target FKBP5 could offer a new way to improve recovery after spinal cord injury.
Insights
FK506-binding protein 5 (FKBP5) initially worsens spinal cord injury by promoting inflammation. Later, it switches to promote healing by altering microglia function and reducing neuronal death, suggesting timed FKBP5 therapies for recovery.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Spinal cord injury (SCI) leads to permanent disability due to limited repair mechanisms.
- The role of FK506-binding protein 5 (FKBP5) in SCI, particularly its dual function in inflammation and repair, remains unclear.
Purpose of the Study:
- To investigate the stage-specific effects of FKBP5 on microglia following spinal cord injury in a mouse model.
- To elucidate the molecular mechanisms underlying FKBP5's dual role in SCI pathogenesis and recovery.
Main Methods:
- Analysis of FKBP5 expression and its interaction with GPR84 and LDHA in microglia post-SCI.
- Assessment of inflammatory markers (interleukin-1β) and neuronal cell death pathways.
- Investigation of lactate metabolism, histone lactylation, and gene expression (Fxyd5, Lgals1) in microglia.
Main Results:
- Early after SCI, FKBP5 and GPR84 synergistically increase interleukin-1β, promoting microglial inflammation and neuronal death.
- Later, elevated FKBP5 modifies LDHA, altering lactate processing and leading to histone lactylation.
- This molecular shift activates protective genes (Fxyd5, Lgals1), converting microglia to a pro-repair phenotype, reducing neuronal death, and enhancing tissue repair.
Conclusions:
- FKBP5 exhibits a dichotomous role in spinal cord injury, initially exacerbating damage and subsequently promoting repair.
- Targeting FKBP5 with precisely timed therapeutic interventions may represent a novel strategy to improve functional recovery after SCI.
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