Peripheral Nerve Injury Induces an Interferon-Responsive State Centered on Satellite Glial Cells in the DRG That Sustains Neuropathic Pain Through STAT1 and CXCL10 Signaling.

Background

Peripheral nerve injury drives persistent remodeling of the dorsal root ganglion (DRG) microenvironment, but the cellular states and intercellular signaling mechanisms that sustain neuropathic pain remain poorly understood.

Methods

Here, we integrated single-cell transcriptomics with histological, behavioral, and electrophysiological approaches to identify an interferon-responsive state in satellite glial cells (SGCs) of the DRG following spared nerve injury (SNI).

Results

This state was distinguished by STAT1-associated interferon-responsive genes' activation and enhanced chemokine signaling, particularly involving CXCL10 and its receptor CXCR3. These molecular alterations were accompanied by remodeling of intercellular communication among SGCs, sensory neurons, and immune cells. Pharmacological inhibition of STAT1 or blockade of CXCR3 not only reduced sensory-neuron hyperexcitability but also attenuated pain hypersensitivity and improved deficits in hindlimb weight bearing and gait after SNI.

Conclusions

Collectively, our findings indicate that interferon-responsive SGCs (IFN SGCs) contribute to the maintenance of neuropathic pain by regulating STAT1-dependent chemokine signaling in the DRG. Targeting this signaling pathway may provide a therapeutic strategy for persistent neuropathic pain.