Lysophosphatidic acid propagates post-injury Schwann cell dedifferentiation through LPA₁ signaling

Lysophosphatidic acid (LPA) is a pleiotropic signaling lipid that acts as ligand for at least six specific G-protein coupled receptors. Schwann cells (SC) are known to mainly express the LPA₁ receptor subtype. An emerging body of evidence has linked LPA with injury-induced peripheral nerve demyelination as well as neuropathic pain. However, the molecular mechanisms underlying its demyelinating effect have not been conclusively elucidated. We aimed to decipher the demyelinating effect in vitro as well as in vivo by studying markers of SC differentiation and dedifferentiation: Myelinated dorsal root ganglia (DRG) cultures were treated either with LPA, LPA plus AM095 (LPA₁ antagonist) or vehicle. Myelin content was subsequently investigated by Sudan Black staining and immunocytochemistry. In vivo, we performed sciatic nerve crush in C57BL/6 mice treated with AM095 at 10mg/kg. In DRG cultures, LPA caused a significant reduction of myelin as demonstrated by both Sudan Black staining and immunocytochemical analysis of myelin basic protein. Demyelination was paralleled by an upregulation of TNF-alpha as well as downregulation of Sox10, a marker for SC differentiation. LPA mediated effects were largely blocked by the addition of the LPA₁ receptor antagonist AM095. In the in vivo model, AM095 treatment prior to crush injury increased Sox10 expression in SCs in the distal nerve stump while reducing the number of cells expressing the SC dedifferentiation marker Sox2. Additionally, TNF-alpha immunofluorescence was reduced in CD11b-positive cells. These data indicate that LPA may be a critical factor that shifts SCs towards a post-injury phenotype and contributes to the onset of Wallerian degeneration.