Schwann cell-derived Apolipoprotein D controls the dynamics of post-injury myelin recognition and degradation

Abstract

Management of lipids, particularly signaling lipids that control neuroinflammation, is crucial for the regeneration capability of a damaged nervous system. Knowledge of pro- and anti-inflammatory signals after nervous system injury is extensive, most of them being proteins acting through well-known receptors and intracellular cascades. However, the role of lipid binding extracellular proteins able to modify the fate of lipids released after injury is not well understood. Apolipoprotein D (ApoD) is an extracellular lipid binding protein of the Lipocalin family induced upon nervous system injury. Our previous study shows that axon regeneration is delayed without ApoD, and suggests its participation in early events during Wallerian degeneration. Here we demonstrate that ApoD is expressed by myelinating and non-myelinating Schwann cells and is induced early upon nerve injury. We show that ApoD, known to bind arachidonic acid (AA), also interacts with lysophosphatidylcholine (LPC) in vitro. We use an in vivo model of nerve crush injury, a nerve explant injury model, and cultured macrophages exposed to purified myelin, to uncover that: (i) ApoD regulates denervated Schwann cell-macrophage signaling, dampening MCP1- and Tnf-dependent macrophage recruitment and activation upon injury; (ii) ApoD controls the over-expression of the phagocytosis activator Galectin-3 by infiltrated macrophages; (iii) ApoD controls the basal and injury-triggered levels of LPC and AA; (iv) ApoD modifies the dynamics of myelin-macrophage interaction, favoring the initiation of phagocytosis and promoting myelin degradation. Regulation of macrophage behavior by Schwann-derived ApoD is therefore a key mechanism conditioning nerve injury resolution. These results place ApoD as a lipid binding protein controlling the signals exchanged between glia, neurons and blood-borne cells during nerve recovery after injury, and open the possibility for a therapeutic use of ApoD as a regeneration-promoting agent.

Neurophagy, the phagocytosis of live neurons and synapses by glia, contributes to brain development and disease

“…This suggests the possibility that demyelination is driven by phagocytosis of intact myelin encouraged by these opsonins. In peripheral nerve cell injury, apolipoprotein D is released and apparently acts as an opsonin to promote macrophage phagocytosis of intact myelin . Injury of spinal cord neurons apparently results in microglia phagocytosing intact myelin, which is prevented by blocking the microglial P2Y12 receptor .…”

Myelin extracellular leaflet compaction requires apolipoprotein D membrane management to optimize lysosomal‐dependent recycling and glycocalyx removal

“…A lysosomal population with these properties would be the perfect candidate to manage glycocalyx remodeling and myelin membrane recycling. This unexpected relationship of ApoD with such a subset of lysosomes, and the evidences that myelin built in an ApoD‐KO background must have different properties altering myelin recognition and digestion by phagocytic cells (Garcia‐Mateo et al, ; Pascua‐Maestro et al, ), led us to study the role of ApoD in the development and maturation of myelin.…”

“…We have recently discovered that the Lipocalin Apolipoprotein D (ApoD), already known to be required for adequate myelin management after PNS injury (Ganfornina et al, ; Garcia‐Mateo et al, ), is targeted to lysosomes in astrocytes and neurons, and is required for lysosomal membrane stability and pH homeostasis (Pascua‐Maestro, Diez‐Hermano, Lillo, Ganfornina, & Sanchez, ). The pH distribution of the subset of ApoD‐positive lysosomes is in the range of optimal pH for neuraminidases, also coincident with that of secretory lysosomes.…”

Aging without Apolipoprotein D: Molecular and cellular modifications in the hippocampus and cortex

“…At the cellular and organismal levels, this lipocalin has been proven to have various functions: protection from oxidative stress through lipid peroxide reduction (Bajo-Graneras et al, 2011a,b;Bhatia et al, 2011Bhatia et al, , 2013Ganfornina et al, 2008), neuronal differentiation (Kosacka et al, 2010;Ruiz et al, 2013) and regeneration of damaged nerves (Ganfornina et al, 2010;Garcia-Mateo et al, 2014). However, in spite of the established link between ApoD and aging, mostly with the aging nervous system, an experimental test causally associating ApoD to mammalian longevity or brain aging is still missing.…”