Genetic deletion of the glucocorticoid receptor in Cx3cr1+ myeloid cells is neuroprotective and improves motor recovery after spinal cord injury

Exp Neurol, 2022 · DOI: 10.1016/j.expneurol.2022.114114 · Published: September 1, 2022

Simple Explanation

Glucocorticoid receptors (GRs) are proteins found in all cell types that respond to stress hormones. In immune cells, GRs can either increase or decrease gene activity, affecting inflammation. This study investigated the impact of removing GRs from specific immune cells (myeloid cells) in mice following spinal cord injury (SCI). Contrary to what was expected, deleting GRs in these cells led to reduced inflammation and improved recovery. The absence of GRs in myeloid cells resulted in less efficient clearance of damaged myelin and lipids, which unexpectedly protected nerve fibers, blood vessels, and improved motor function after SCI.

Study Duration

5 weeks

Participants

Mice (MØ GR intact and MØ GR deleted groups)

Evidence Level

Not specified

Key Findings

1
Deleting GR in myeloid cells (macrophages and microglia) reduced the inflammatory response in the spinal cord after injury.
2
Mice with GR deleted in myeloid cells showed improved hindlimb motor recovery after spinal cord injury.
3
Deleting GR in myeloid cells resulted in neuroprotection, including greater myelin and axon sparing, and increased vascular protection/regeneration.

Research Summary

This study investigated the role of glucocorticoid receptors (GRs) in myeloid cells after spinal cord injury (SCI). Contrary to the hypothesis that deleting GR would worsen outcomes, the study found that deleting GR in myeloid cells led to reduced inflammation and improved motor recovery. The key findings included reduced macrophage accumulation, improved myelin and axon sparing, increased vascular protection, and decreased lipid phagocytosis in mice with GR deleted in myeloid cells. The authors suggest that endogenous GR signaling in macrophages normally limits their ability to carry out repair functions in the injured central nervous system (CNS), and that therapies using exogenous glucocorticoids may exacerbate this inhibition.

Practical Implications

Therapeutic Target

Targeting GR signaling in macrophages could be a novel therapeutic approach to improve recovery after SCI.

GC Therapy Re-evaluation

The use of glucocorticoids as a standard treatment for SCI should be re-evaluated, considering their potential to inhibit macrophage-mediated repair.

Neurodegenerative Applications

Selective deletion of macrophage GR could enhance macrophage-mediated repair in other neurodegenerative or demyelinating disorders.

Study Limitations

1
Limited mechanistic insight into how GR deletion confers neuroprotection.
2
Cannot distinguish the specific contributions of microglia versus monocyte-derived macrophages due to the use of Cx3cr1-Cre mice.
3
Study design as exploratory study limits comprehensive insight.

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