FKBP5 Orchestrates a Biphasic Microglial Response in Spinal Cord Injury by Sequentially Activating the GPR84/IL-1β Pathway and the LDHA-Lactylation-FXYD5/LGALS1 Axis.

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.