119: Sensory Neuron Derived Interleukin-34 Modulates Macrophages in Neonatal Nociceptive Priming

Topic: Basic Science
Subtopic: Pain category (ICD-11), Acute musculoskeletal pain, , , , , , , , , , Neuroimmunology, Animal imaging (includes Ca2+ imaging, fluorescence microscopy), Behavioral studies

Background and Aims: Injury to the developing peripheral nervous system can lead to prolonged hypersensitivity after repeated injury later in life; a phenomenon called neonatal nociceptive priming. Macrophages have recently been found to be key drivers of this phenomenon. After early-life injury, peripheral macrophages retain epigenetic modifications and generate a more pro-inflammatory response to subsequent injury that contributes to prolonged pain-like responses. However, it is not known whether sensory neurons themselves establish similar “memories” of early life injury and therefore also contribute to neonatal nociceptive priming.

Methods: We performed ATAC-Seq on DRGs isolated from neonatal and adolescent mice that received an early-life injury and compared them to uninjured adolescent DRGs. Multiple genes showed increased chromatin accessibility after early-life injury and were maintained into adolescence including cytokines like Interleukin-34(IL34). To reduce neuronal IL34 mRNA, we utilized a nerve targeted siRNA knockdown strategy and performed behavioral assays. We investigated IL34 knockdown effects on macrophage infiltration and inflammatory profile using immunofluorescence and cytokine arrays. Neuronal sensitization after IL34 knockdown was determined using ex-vivo calcium imaging. We performed Homer analysis on the accessible chromatin region of IL34 to determine potential mechanisms.

Results: Neuronal IL34 knock down blocked behavioral hypersensitivity following repeated injury and inhibited mechanical and chemical sensitization in primary afferents. We found that neuronal IL34 regulated macrophage populations in the muscle but not DRG following repeated injury. IL34 also altered the inflammatory profile in the periphery following repeated injury. Homer analysis revealed that transcription factor Nuclear Receptor Subfamily 2 Group F Member 2 (Nr2f2) can bind the accessible IL34 region. In vitro and in vivo assays showed that injury or simulated injury (TNFα treatment) on sensory neurons had significant reduction of Nr2f2 mRNA.

Conclusions: There are key development periods where the immune and somatosensory systems are vulnerable to “priming”, leaving children at risk for hypersensitivity following early-life surgeries. The current work identifies a novel mechanism highlighting the sensory neuron contribution to neonatal nociceptive priming and reveals a new potential treatment strategy for chronic post-surgical pain in children.

References: Dourson AJ, Fadaka AO, Warshak AM, et al. Macrophage memories of early-life injury drive neonatal nociceptive priming. Cell Rep. 2024;43(5):114129. doi:10.1016/j.celrep.2024.114129
Dourson AJ, Jankowski MP. Developmental impact of peripheral injury on neuroimmune signaling. Brain Behav Immun. 2023;113:156-165. doi:10.1016/j.bbi.2023.07.002

Presenting Author: Kourtney L. Sprague
Submitting Author: Kourtney Sprague

Senior Author: Michael P. Jankowski

IASP 2026 Global Year theme of Neuropathic Pain: No

• Namrata G.R. Raut: Ph.D. - Cincinnati Children's Medical Center
• Adewale O. Fadaka: Ph.D. - Cincinnati Children's Medical Center
• Aaditya Adlakha: M.S. - Cincinnati Children's Medical Center
• Evelyn M. Astafiev-Holmes: B.S. - Cincinnati Children's Medical Center