Lack of galectin-3 speeds Wallerian degeneration by altering TLR and pro-inflammatory cytokine expressions in injured sciatic nerve

Wallerian degeneration (WD) comprises a series of events that includes activation of non‐neuronal cells and recruitment of immune cells, creating an inflammatory milieu that leads to extensive nerve fragmentation and subsequent clearance of the myelin debris, both of which are necessary prerequisites for effective nerve regeneration. Previously, we documented accelerated axon regeneration in animals lacking galectin‐3 (Gal‐3), a molecule associated with myelin clearance. To clarify the mechanisms underlying this enhanced regeneration, we focus here on the early steps of WD following sciatic nerve crush in Gal‐3−/− mice. Using an in vivo model of nerve degeneration, we observed that removal of myelin debris is more efficient in Gal‐3−/− than in wild‐type (WT) mice; we next used an in vitro phagocytosis assay to document that the phagocytic potential of macrophages and Schwann cells was enhanced in the Gal‐3−/− mice. Moreover, both RNA and protein levels for the pro‐inflammatory cytokines IL‐1β and TNF‐α, as well as for Toll‐like receptor (TLR)‐2 and ‐4, show robust increases in injured nerves from Gal‐3−/−mice compared to those from WT mice. Collectively, these data indicate that the lack of Gal‐3 results in an augmented inflammatory profile that involves the TLR–cytokine pathway, and increases the phagocytic capacity of Schwann cells and macrophages, which ultimately contributes to speeding the course of WD. The lack of Gal‐3 after sciatic nerve injury speeds Wallerian degeneration (WD) by augmenting the inflammatory profile of WD and by accelerating myelin breakdown and clearance. In addition, the absence of Gal‐3 in macrophages and Schwann cells results in an improvement in their phagocytic potential.