Abstract
BackgroundA unique feature of the pathological change after spinal cord injury (SCI) is the progressive enlargement of lesion area, which usually results in cavity formation and is accompanied by reactive astrogliosis and chronic inflammation. Reactive astrocytes line the spinal cavity, walling off the lesion core from the normal spinal tissue, and are thought to play multiple important roles in SCI. The contribution of cell death, particularly the apoptosis of neurons and oligodendrocytes during the process of cavitation has been extensively studied. However, how reactive astrocytes are eliminated following SCI remains largely unclear.ResultsBy immunohistochemistry, in vivo propidium iodide (PI)-labeling and electron microscopic examination, here we reported that in mice, reactive astrocytes died by receptor-interacting protein 3 and mixed lineage kinase domain-like protein (RIP3/MLKL) mediated necroptosis, rather than apoptosis or autophagy. Inhibiting receptor-interacting protein 1 (RIP1) or depleting RIP3 not only significantly attenuated astrocyte death but also rescued the neurotrophic function of astrocytes. The astrocytic expression of necroptotic markers followed the polarization of M1 microglia/macrophages after SCI. Depleting M1 microglia/macrophages or transplantation of M1 macrophages could significantly reduce or increase the necroptosis of astrocytes. Further, the inflammatory responsive genes Toll-like receptor 4 (TLR4) and myeloid differentiation primary response gene 88 (MyD88) are induced in necroptotic astrocytes. In vitro antagonizing MyD88 in astrocytes could significantly alleviate the M1 microglia/macrophages-induced cell death. Finally, our data showed that in human, necroptotic markers and TLR4/MyD88 were co-expressed in astrocytes of injured, but not normal spinal cord.ConclusionTaken together, these results reveal that after SCI, reactive astrocytes undergo M1 microglia/macrophages-induced necroptosis, partially through TLR/MyD88 signaling, and suggest that inhibiting astrocytic necroptosis may be beneficial for preventing secondary SCI.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0081-8) contains supplementary material, which is available to authorized users.
Highlights
A unique feature of the pathological change after spinal cord injury (SCI) is the progressive enlargement of lesion area, which usually results in cavity formation and is accompanied by reactive astrogliosis and chronic inflammation
Because Nec-1 inhibits indoleamine-2,3-dioxygenase (IDO) [24], we used Receptor-interacting protein 3 (RIP3)−/− astrocytes to confirm the occurrence of Inhibiting necroptosis rescues both the death and neurotrophic phenotype of reactive astrocytes after SCI We examined the effects of inhibiting necroptosis on the survival of astrocytes after SCI
We examined the effects of M1 microglia/macrophages on the expression of Toll-like receptor 4 (TLR4) and myeloid differentiation primary response gene 88 (MyD88) in astrocytes
Summary
A unique feature of the pathological change after spinal cord injury (SCI) is the progressive enlargement of lesion area, which usually results in cavity formation and is accompanied by reactive astrogliosis and chronic inflammation. One unique pathological change after primarily spinal cord injury (SCI) is the secondary injury, which is characterized by continuous tissue loss, reactive astrogliosis and chronic inflammation, and usually leads to gradual expansion of the lesion center and formation of a spinal cavity [1, 2]. How reactive astrocytes, which are the major component of the glial scar, play diverse roles in SCI [6] and are important in supporting neuronal survival [6], are eliminated remains poorly investigated. Whether and how the activity of M1 microglia/macrophages affects the survival of reactive astrocytes remains unclear
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