Lysophosphatidic acid receptor type 2 activation contributes to secondary damage after spinal cord injury in mice

Lysophosphatidic acid (LPA) is an extracellular lipid mediator involved in many physiological functions by signaling through six known G-protein-coupled receptors (LPA₁-LPA₆). In the central nervous system (CNS), LPA mediates a wide range of effects, including neural progenitor cell physiology, astrocyte and microglia activation, neuronal cell death, axonal retraction, and contributions to pain, schizophrenia and hydrocephalus. We recently reported that LPA-LPA₁ signaling mediates functional deficits and myelin loss after spinal cord injury (SCI). Here, we provide clear evidence on the deleterious contribution of another LPA receptor, LPA₂, to myelin loss after SCI. We found that LPA₂ is constitutively expressed in the spinal cord parenchyma and its transcripts were up-regulated after contusion injury, in part, by microglial cells. We also found that the demyelinating lesion triggered by intraspinal injection of LPA into the undamaged spinal cord was markedly reduced in the lack of LPA₂. Similarly, LPA₂ deficient mice showed enhanced motor skills and myelin sparing after SCI. To gain insights into the detrimental actions of LPA₂ in spinal cord we performed cell culture studies. These experiments revealed that, similar to LPA₁, activation of microglia LPA₂ led to oligodendrocyte cell death. Moreover, we also found that the cytotoxic effects underlaying microglial LPA-LPA₂ axis were mediated by the release of purines by microglia and the activation of P₂X₇ receptor on oligodendrocytes. Overall, this study provides new mechanistic insights into how LPA contributes to SCI physiopathology, and suggest that targeting LPA₂ could be a novel therapeutic approach for the treatment of acute SCI.