Cytokine polarized, alternatively activated bone marrow neutrophils drive axon regeneration

Nat Immunol. 2024 Jun;25(6):957-968. doi: 10.1038/s41590-024-01836-7. Epub 2024 May 29.

Abstract

The adult central nervous system (CNS) possesses a limited capacity for self-repair. Severed CNS axons typically fail to regrow. There is an unmet need for treatments designed to enhance neuronal viability, facilitate axon regeneration and ultimately restore lost neurological functions to individuals affected by traumatic CNS injury, multiple sclerosis, stroke and other neurological disorders. Here we demonstrate that both mouse and human bone marrow neutrophils, when polarized with a combination of recombinant interleukin-4 (IL-4) and granulocyte colony-stimulating factor (G-CSF), upregulate alternative activation markers and produce an array of growth factors, thereby gaining the capacity to promote neurite outgrowth. Moreover, adoptive transfer of IL-4/G-CSF-polarized bone marrow neutrophils into experimental models of CNS injury triggered substantial axon regeneration within the optic nerve and spinal cord. These findings have far-reaching implications for the future development of autologous myeloid cell-based therapies that may bring us closer to effective solutions for reversing CNS damage.

MeSH terms

  • Adoptive Transfer
  • Animals
  • Axons* / metabolism
  • Axons* / physiology
  • Cells, Cultured
  • Cytokines / metabolism
  • Granulocyte Colony-Stimulating Factor* / metabolism
  • Granulocyte Colony-Stimulating Factor* / pharmacology
  • Humans
  • Interleukin-4* / metabolism
  • Mice
  • Mice, Inbred C57BL*
  • Nerve Regeneration* / immunology
  • Neutrophil Activation
  • Neutrophils* / immunology
  • Spinal Cord Injuries / immunology
  • Spinal Cord Injuries / metabolism
  • Spinal Cord Injuries / therapy

Substances

  • Granulocyte Colony-Stimulating Factor
  • Interleukin-4
  • Cytokines