Neutrophils Express Oncomodulin and Promote Optic Nerve Regeneration

Abstract

Although neurons are normally unable to regenerate their axons after injury to the CNS, this situation can be partially reversed by activating the innate immune system. In a widely studied instance of this phenomenon, proinflammatory agents have been shown to cause retinal ganglion cells, the projection neurons of the eye, to regenerate lengthy axons through the injured optic nerve. However, the role of different molecules and cell populations in mediating this phenomenon remains unclear. We show here that neutrophils, the first responders of the innate immune system, play a central role in inflammation-induced regeneration. Numerous neutrophils enter the mouse eye within a few hours of inducing an inflammatory reaction and express high levels of the atypical growth factor oncomodulin (Ocm). Immunodepletion of neutrophils diminished Ocm levels in the eye without altering levels of CNTF, leukemia inhibitory factor, or IL-6, and suppressed the proregenerative effects of inflammation. A peptide antagonist of Ocm suppressed regeneration as effectively as neutrophil depletion. Macrophages enter the eye later in the inflammatory process but appear to be insufficient to stimulate extensive regeneration in the absence of neutrophils. These data provide the first evidence that neutrophils are a major source of Ocm and can promote axon regeneration in the CNS.

Critical Role of the CXCL10/C-X-C Chemokine Receptor 3 Axis in Promoting Leukocyte Recruitment and Neuronal Injury during Traumatic Optic Neuropathy Induced by Optic Nerve Crush

“…73 However, protective and regenerative roles of neutrophils are also reported in certain conditions. 73,74 Myeloid cells also differentially affect tissue injury, depending on their phenotypes. Macrophages are proinflammatory and cause tissue injury when they are polarized into the M1 phenotype, whereas they are antiinflammatory and promote tissue repair and regeneration in the M2 phenotype.…”

Cell biology of spinal cord injury and repair

“…Activated macrophages induce retraction and dieback of axons after SCI (77). In contrast, neutrophils around neuronal cell bodies can stimulate axon regeneration (78). More work is needed on understanding how inflammatory cells influence axon regrowth.…”

Neuroinflammation triggered by β-glucan/dectin-1 signaling enables CNS axon regeneration

“…This phenomenon is not restricted to the visual system, because injection of zymosan into dorsal root ganglia or spinal cord parenchyma triggers local inflammation and growth of injured or transplanted sensory neurons (9,10). Macrophages (3,9), neutrophils (11), and astrocytes (12) have been implicated in the proregenerative effects of inflammation. The benefits of neuroinflammation on axonal growth can be undermined by concurrent toxicity (9).…”