Granulocyte-colony-stimulating factor (G-CSF) signaling in spinal microglia drives visceral sensitization following colitis
| Autor: | Morley D. Hollenberg, Mircea Iftinca, Candace M. Marsters, Lilian Basso, Deborah M. Kurrasch, Tamia K. Lapointe, Christophe Altier |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
CX3C Chemokine Receptor 1 Nitric Oxide Synthase Type II Proinflammatory cytokine Cell Line 03 medical and health sciences 0302 clinical medicine Dorsal root ganglion Ganglia Spinal CX3CR1 Granulocyte Colony-Stimulating Factor medicine Animals Colitis Sensitization Multidisciplinary Microglia business.industry Dextran Sulfate Visceral pain Visceral Pain Biological Sciences medicine.disease Cathepsins Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Spinal Cord Immunology Receptors Granulocyte Colony-Stimulating Factor Nociceptor medicine.symptom business 030217 neurology & neurosurgery |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 114(42) |
| ISSN: | 1091-6490 |
| Popis: | Pain is a main symptom of inflammatory diseases and often persists beyond clinical remission. Although we have a good understanding of the mechanisms of sensitization at the periphery during inflammation, little is known about the mediators that drive central sensitization. Recent reports have identified hematopoietic colony-stimulating factors as important regulators of tumor- and nerve injury-associated pain. Using a mouse model of colitis, we identify the proinflammatory cytokine granulocyte-colony–stimulating factor (G-CSF or Csf-3) as a key mediator of visceral sensitization. We report that G-CSF is specifically up-regulated in the thoracolumbar spinal cord of colitis-affected mice. Our results show that resident spinal microglia express the G-CSF receptor and that G-CSF signaling mediates microglial activation following colitis. Furthermore, healthy mice subjected to intrathecal injection of G-CSF exhibit pronounced visceral hypersensitivity, an effect that is abolished by microglial depletion. Mechanistically, we demonstrate that G-CSF injection increases Cathepsin S activity in spinal cord tissues. When cocultured with microglia BV-2 cells exposed to G-CSF, dorsal root ganglion (DRG) nociceptors become hyperexcitable. Blocking CX3CR1 or nitric oxide production during G-CSF treatment reduces excitability and G-CSF–induced visceral pain in vivo. Finally, administration of G-CSF–neutralizing antibody can prevent the establishment of persistent visceral pain postcolitis. Overall, our work uncovers a DRG neuron–microglia interaction that responds to G-CSF by engaging Cathepsin S-CX3CR1-inducible NOS signaling. This interaction represents a central step in visceral sensitization following colonic inflammation, thereby identifying spinal G-CSF as a target for treating chronic abdominal pain. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|