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

Abstract

Highlights What are the main findings? SNI induces a distinct STAT1-associated IFN SGC population in the DRG, characterized by increased CXCL10 expression. This SGC inflammatory program is associated with sensory-neuron hyperexcitability and pain hypersensitivity. Local STAT1 inhibition or CXCR3 blockade alleviates pain. What are the implications of the main findings? SGCs may actively shape the DRG inflammatory microenvironment and drive neuronal sensitization after nerve injury. The STAT1–CXCL10–CXCR3 axis is a potential local therapeutic target for neuropathic pain and injury-related functional impairment. Abstract 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.