# FKBP5 regulates interferon signaling leading to myeloid cell activation in multiple sclerosis

## TL;DR

This study shows that FKBP5 plays a key role in myeloid cell activation in multiple sclerosis and could be a new therapeutic target.

## Contribution

The study identifies FKBP5 as a novel regulator of interferon signaling and myeloid cell function in MS.

## Key findings

- FKBP5 is elevated in MS patient monocytes and microglial nodules.
- Inhibiting FKBP5 improves myelin clearance and reduces IFNg signaling in EAE models.
- FKBP5 inhibition leads to reduced immune infiltration and better clinical outcomes in MS.

## Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by immune-mediated demyelination and axonal injury. Recent works have highlighted the critical role of myeloid cells in MS, contributing to both neurodegeneration and repair. FK506-binding protein 5 (FKBP5), a co-chaperone of the glucocorticoid receptor and regulator of stress responses, has been implicated in MS pathology, yet its mechanistic role remains poorly understood. Here, we show that FKBP5 expression is elevated in monocytes and dendritic cells from the cerebrospinal fluid of people with MS and enriched in microglial nodules. Additionally, we show that genetic ablation or pharmacological inhibition of Fkbp5 in microglia and macrophages enhances myelin uptake and degradation via phagolysosomal pathways and attenuates interferon-gamma (IFNg)-induced transcriptional programs. In the experimental autoimmune encephalomyelitis (EAE) model of MS, systemic treatment with the selective FKBP5 inhibitor SAFit2 reduced immune cell infiltration, dampened microglial activation, and suppressed IFNg signaling, resulting in improved clinical outcomes. Taken together, our data identify FKBP5 as a critical mediator of myeloid cell-driven neuroinflammation, and a promising therapeutic target in MS.

The online version contains supplementary material available at 10.1186/s12974-026-03703-8.