Reactive astrocytes undergo M1 microglia/macrohpages-induced necroptosis in spinal cord injury

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.

Necroptosis: Mechanisms and Relevance to Disease

“…Nec-1 mediates neuroprotective effects in rodent models of acute and chronic neurological conditions, including adult stroke (146), neonatal hypoxia/ischemia (H/I) (147, 148), retinal ischemia (149), retinal detachment (150–152), subarachnoid hemorrhage (153, 154), traumatic brain injury (155), spinal cord injury (156–159), and amyotrophic lateral sclerosis (160). The ability of Nec-1 to counteract manifestations of amyotrophic lateral sclerosis in mice was backed up by the knockdown of RIPK1 as well as by data obtained using human cells treated with necrosulfonamide (NSA, a chemical that inhibits human MLKL) (160).…”

“…As notable exceptions, Ripk3 −/− mice exhibit an increased resistance to retinal detachment triggered by subretinal injections of sodium hyaluronate (150) or polyI:C (152), as compared with their WT littermates. Similarly, Ripk3 −/− mice exhibit a sizeable reduction in astrocytic demise upon spinal cord injury as compared with WT mice, which correlates with an improved preservation of neurotrophic function (159). Moreover, the administration of a Ripk3 -targeting siRNA limits the demise of outer hair cells exposed to noise that causes a permanent threshold shift in hearing, an otoprotective effect that can be increased by the concomitant administration of Z-VAD-fmk (161).…”

A Mini Review on My Study of the Spinal Cord Injury

“…This is a simple experiment with great clinical significance. Since there is no harm done if the hemostatic drug is carefully chosen, the first thing to do in handling spinal cord injury accidence should be an immediate injection of hemostatic drug, which is particularly important in cases of massive accidents [29,30].…”

Necropotosis: a new link between cell death and inflammation

“…[33,34] Our recent studies demonstrated that RIP3 and phosphorylated MLKL are up-regulated in reactive astrocytes and microglia after SCI. [35,36] Reactive astrocytes, which line the spinal cavity, die by M1 microglia/macrophage induced necroptosis partially through toll like receptor/myeloid differentiation 88 signalling. [35] Microglia, the major player of chronic inflammation post-SCI, die through endoplasmic reticulum stress involved necroptosis.…”

“…[35,36] Reactive astrocytes, which line the spinal cavity, die by M1 microglia/macrophage induced necroptosis partially through toll like receptor/myeloid differentiation 88 signalling. [35] Microglia, the major player of chronic inflammation post-SCI, die through endoplasmic reticulum stress involved necroptosis. [36] These researches raised the straightforward question of how necroptosis regulateschronic inflammation after SCI.…”