Oxidized Galectin-1 Stimulates Macrophages to Promote Axonal Regeneration in Peripheral Nerves after Axotomy

Abstract

Various neurotrophic factors that promote axonal regeneration have been investigated in vivo, but the signals that prompt neurons to send out processes in peripheral nerves after axotomy are not well understood. Previously, we have shown oxidized galectin-1 (GAL-1/Ox) promotes initial axonal growth after axotomy in peripheral nerves. However, the mechanism by which GAL-1/Ox promotes axonal regeneration remains unclear and is the subject of the present study. To identify possible target cells of GAL-1/Ox, a fluorescently labeled recombinant human GAL-1/Ox (rhGAL-1/Ox) was incubated with DRG neurons, Schwann cells, and intraperitoneal macrophages from adult rats. Only the cell surfaces of intraperitoneal macrophages bound the rhGAL-1/Ox, suggesting that these cells possess a receptor for GAL-1/Ox. Experiments examining tyrosine phosphorylation revealed that rhGAL-1/Ox stimulated changes in signal transduction pathways in these macrophages. These changes caused macrophages to secrete an axonal growth-promoting factor. This was demonstrated when conditioned media of macrophages stimulated with rhGAL-1/Ox in 48 hr culture strongly enhanced axonal regeneration from transected-nerve sites of DRG explants. Furthermore, activated macrophage-conditioned media also improved Schwann cell migration from the transected-nerve sites. From these results, we propose that axonal regeneration occurs in axotomized peripheral nerves as a result of cytosolic reduced galectin-1 being released from Schwann cells and injured axons, which then becomes oxidized in the extracellular space. Oxidized galectin-1 then stimulates macrophages to secrete a factor that promotes axonal growth and Schwann cell migration, thus enhancing peripheral nerve regeneration.

Galectin-1 promotes basal and kainate-induced proliferation of neural progenitors in the dentate gyrus of adult mouse hippocampus

“…20,33 It has been shown that oxidized galectin-1 acts directly on macrophages, which in turn may produce a factor that promotes axonal growth. 33 We have shown earlier that exposure to kainate significantly increases oxidative stress in the hippocampus and that oxidative damage of cellular components is accumulated in hippocampal neurons, astrocytes, and microglias. 21 Therefore, we suggest that astrocytesecreted galectin-1, which is likely to be mostly oxidized, may function in promoting neurogenesis in the dentate gyrus.…”

Pancreatitis-Associated Protein-III Is a Novel Macrophage Chemoattractant Implicated in Nerve Regeneration

“…Accumulated macrophages after PNS injury, for example, produce Schwann cell migration factor (Horie et al, 2004) survival, e.g., brain-derived neurotrophic factor (BDNF), interleukin (IL)-6, or glial cell line-derived neurotrophic factor (Batchelor et al, 1999;Dougherty et al, 2000;Leskovar et al, 2000). In fact, BDNF is especially shown to be involved in collateral branching from regenerating motor axons (Streppel et al, 2002).…”

Galectin-1β, a natural monomeric form of galectin-1 lacking its six amino-terminal residues promotes axonal regeneration but not cell death

“…41 In vitro studies using DRG explants revealed that oxidized Gal-1a directly stimulates macrophages to secrete a factor that promotes axonal growth; 42 however, many important questions remain to be answered. Concerning Gal-1b, we must clarify whether or not Gal-1b also acts on macrophages, and whether the oxidation of cysteine residues in Gal-1b is required for such regeneration.…”