727: Interleukin 1 Receptor Antagonist Regulates Nerve to Sensory Neuron Signaling in Regeneration

Topic: Basic Science
Subtopic: Non-specific to any diagnosis (including studies in healthy animals), Neuroimmunology, Pharmacological interventions, Behavioral studies

Background and Aims: Peripheral nerve injury triggers a robust inflammatory response that shapes axonal regeneration and functional recovery. Interleukin-1 signaling is a central mediator of neuroimmune communication between injured peripheral nerves and sensory neurons in the dorsal root ganglion. However, the role of its endogenous inhibitor, the interleukin-1 receptor antagonist, in regulating regenerative signaling remains unclear. We hypothesized that interleukin-1 receptor antagonist modulates inflammation-driven neuronal growth responses following nerve injury. The aim of this study was to determine whether modulation of interleukin-1 receptor antagonist alters cytokine expression within the injured nerve microenvironment and dorsal root ganglion, and to assess its effects on axonal regeneration and sensory outcomes. By integrating cytokine profiling, molecular analysis, and functional measurements, we sought to define the contribution of interleukin-1 receptor antagonist to neuroimmune signaling during peripheral nerve regeneration.

Methods: Adult mice underwent sciatic nerve crush injury and were analyzed at 7 days post-injury. Animals received the interleukin-1 receptor antagonist Anakinra or vehicle control. Injured sciatic nerve and dorsal root ganglion tissues were collected for cytokine profiling, immunofluorescence, and immunoblot analyses. Cytokine expression was assessed using a membrane-based multiplex array and validated by quantitative analyses. Neutrophil infiltration and extracellular trap formation were evaluated using Ly6G, citrullinated histone H3, and myeloperoxidase staining, with spatial organization quantified from confocal images. Primary dorsal root ganglion neurons were cultured and treated with neutrophil extracellular trap–conditioned media with or without DNase I or Anakinra, followed by neurite outgrowth analysis, immunoblotting, and calcium imaging. Public single-cell RNA sequencing datasets were analyzed using integrative approaches to assess cell-type–specific inflammatory signaling. Statistical analyses were performed using appropriate parametric or non-parametric tests.

Results: Sciatic nerve injury induced a dominant interleukin-1 signaling program within the nerve microenvironment, characterized by robust upregulation of interleukin-1 receptor antagonist and related cytokines. Single-cell transcriptomic analysis and immunostaining localized interleukin-1 receptor antagonist expression to infiltrating myeloid populations following injury. This inflammatory response was associated with marked neutrophil recruitment and the formation of spatially organized neutrophil extracellular traps, both of which were significantly reduced by interleukin-1 receptor blockade. In vitro, conditioned media derived from extracellular traps impaired neurite outgrowth and increased neuronal excitability, accompanied by activation of extracellular signal–regulated kinase and nuclear factor kappa B signaling in dorsal root ganglion neurons. These effects were attenuated by DNase treatment and suppressed by interleukin-1 receptor antagonism. In vivo, targeting the interleukin-1–extracellular trap axis enhanced axonal regeneration and improved mechanical and thermal sensitivity following nerve injury. Together, these findings identify interleukin-1–dependent neuroimmune signaling as a key regulator of neuronal function and regeneration.

Conclusions: Our findings establish interleukin-1–dependent neuroimmune signaling as a central regulator of the post-injury nerve microenvironment. We identify a pathway in which injury-induced interleukin-1 activity drives neutrophil recruitment and extracellular trap formation, which in turn disrupt neuronal structure and promote hyperexcitability. Pharmacological blockade of interleukin-1 signaling suppresses this inflammatory cascade, restores neuronal integrity, and enhances axonal regeneration and sensory recovery. These results define a mechanistic link between cytokine signaling, innate immune activation, and neuronal repair, revealing the interleukin-1–extracellular trap axis as a critical checkpoint in peripheral nerve regeneration. Targeting this pathway provides a rational strategy to modulate neuroimmune interactions and improve outcomes following nerve injury.

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Presenting Author: Emmanuel Acquah
Submitting Author: Emmanuel Acquah

Senior Author: Euiheon Chung

IASP 2026 Global Year theme of Neuropathic Pain: Yes

• An Nazmus Sakib: MSc. - GIST
• Euiheon Chung: PhD - GIST