The cell-specific effects of the human remyelination-promoting rHIgM22 on sphingolipid metabolism in cultured glial cells

Abstract

Demyelinating diseases are heterogeneous in their etiology, clinical course, and manifestations. In the long run, however, they lead to irreversible dysfunction of the nervous system. Although myelin regeneration occurs in response to myelin damage in both animal models of demyelination and human patients, the outcome is usually less favorable in humans. This explains the interest in treatments that could improve the effectiveness of myelin regeneration. Among these, treatment with the monoclonal antibody rHIgM22 has been shown to effectively enhance myelin regeneration in both immune and non-immune mouse models of demyelination. Its administration to patients with multiple sclerosis was well tolerated, and it was detected in the cerebrospinal fluid, suggesting penetration of the central nervous system. Previously, we demonstrated that administering rHIgM22 to rat mixed glial cultures alters the balance between ceramide and sphingosine 1-phosphate (S1P), thereby inducing S1P release and astrocyte and oligodendrocyte precursor cell (OPC) proliferation. In this paper, we studied the effects of rHIgM22 treatment on the lipid composition of purified glial cultures from the rat brain, including astrocytes, OPC, and oligodendrocytes (OL) at various stages of in vitrodifferentiation. rHIgM22 did not affect the phospholipid composition of any of the analyzed cell types. A steady-state metabolic labeling procedure revealed that sphingolipid patterns were unaffected by rHIgM22 treatment in astrocytes. However, rHIgM22 treatment significantly increased the levels of GM3 and GD3 gangliosides in oligodendroglial cells. The increase in GM3 and GD3 versus controls was highest in fully differentiated OL. We also detected a slight but significant reduction in cholesterol levels and in vitro acid sphingomyelinase activity in these cells. Acid sphingomyelinase is a key enzyme in sphingolipid metabolism. Thus, the effect of rHIgM22 on lipid metabolism is cell-specific among different glial populations. We hypothesize that the myelin regeneration effects of rHIgM22 could result from alterations in lipid-dependent membrane organization in oligodendroglial cells.