Peripheral nerve injury induces Schwann cells to express two macrophage phenotypes: phagocytosis and the galactose-specific lectin MAC-2

Abstract

In N mice, peripheral nerve injury is followed by the normal rapid progression of Wallerian degeneration: Schwann cells proliferate and lose their myelin, which is phagocytized and metabolized by blood-borne macrophages. The role of Schwann cells in myelin phagocytosis is debated. Additionally, the molecular mechanisms underlying myelin phagocytosis by the two cell types are not well understood. To elucidate the role of Schwann cells as phagocytes we studied, electron microscopically, in vivo and in vitro degenerating, frozen, and neuroma nerve segments. The major cell types composing these tissues differed: Schwann and macrophages in in vivo degenerating; Schwann in in vitro degenerating; macrophages in frozen; Schwann, macrophages, and fibroblasts in neuroma nerve segments. Both macrophages and Schwann cells phagocytized myelin. We further studied, by immunocytochemistry and immunoblot analysis, the expression of molecules that are characteristically displayed by inflammatory and mature murine macrophages: MAC-1 (the C3b complement receptor), MAC-2 (a galactose- specific lectin), the Fc receptor, and the F4/80 antigen. All were detected in the macrophage-rich, in vivo degenerating, frozen, and neuroma nerve segments. Surprisingly, MAC-2 was also expressed in the macrophage-scarce, Schwann-rich, in vitro degenerating nerve. Immunocytochemistry and immunoblot analysis of isolated non-neuronal cells revealed that both macrophages and Schwann cells displayed MAC-2 on their surface and in their cytoplasm. Morphometry unveiled that galactose and lactose specifically inhibited myelin phagocytosis, as predicted if MAC-2 was mediating myelin phagocytosis by lectinophagocytosis (lectin-mediated phagocytosis). The role of MAC-2 in mediating myelin phagocytosis was further supported by two observations made in W mice that display very slow progression of Wallerian degeneration. First, the failure to degenerate in vivo was associated with deficient MAC-2 production. Second, degeneration that occurred in vitro was associated with MAC-2 production. Furthermore, a strong positive correlation between levels of MAC-2 expression and the extent of myelin destruction by phagocytosis was observed over a wide range of values.

Phosphorylation of adhesion- and growth-regulatory human galectin-3 leads to the induction of axonal branching by local membrane L1 and ERM redistribution

“…In the nervous system Gal-3 is expressed, among others, by activated Schwann cells after peripheral nerve injury (Reichert et al, 1994) and by olfactory ensheathing cells, as we (data not shown), and others (Storan et al, 2004) have observed. Taking into consideration that both the peripheral nervous system and the olfactory system (CNS) show nerve regeneration capacity, it is tempting to speculate that induction of Gal-3 expression in axon-ensheathing cells could correlate with regenerative activity in the nervous system.…”

“…Having also previously initiated the monitoring of the involvement of galectins in axonal development with two prototype chicken galectins (Kopitz et al, 2004), the access to pGal-3 allows us to address the issue of the functional relevance of Gal-3 phosphorylation in this respect. Of note, Gal-3 is expressed mainly by glial cells (Pesheva et al, 1998;Reichert et al, 1994;Walther et al, 2000) but also by subsets of rat sensory and mouse dorsal root ganglia (DRG) neurons Regan et al, Phosphorylation of adhesion-and growth-regulatory human galectin-3 leads to the induction of axonal branching by local membrane L1 and ERM redistribution 1986). It promotes neural cell adhesion and neurite growth of DRG neurons (Pesheva et al, 1998) and, when covalently cross-linked by transglutaminase activity, it can stabilize the neurites of cerebellar granule cells (Mahoney et al, 2000).…”

A Distinct Pattern of Trophic Factor Expression in Myelin-Deficient Nerves ofTremblerMice: Implications for Trophic Support by Schwann Cells

“…However, the temporal relationships of myelin breakdown or SC proliferation do not coincide with maximum BDNF expression during Wallerian degeneration. The removal of myelin debris is virtually complete 6 d after sciatic nerve transection in mice (Reichert et al, 1994). Furthermore, SC proliferation peaks during the first week after axotomy when BDNF values are only beginning to rise.…”

Human galectins as sensors for apoptosis/necrosis‐associated surface changes of granulocytes and lymphocytes

“…In essence, slight changes in glycan structure and presentation bear upon binding parameters. Further, encouraged by emerging possibility for a role of galectins-1 and -3 in elimination of myelin or injured axons and galectin-3's presence in phagosomes of mouse J774 macrophagelike cells (18)(19)(20)(21), we thus hypothesized that cell surface changes associated with cell death become detectable by these endogenous lectins, and that their reactivity may depend on the type of lectin and death program. To address this issue properly, we used an established system for the induction of cell death in human blood cells (9) and a panel of human galectins, deliberately including members of each subfamily.…”