Picture yourself being immobilized, in a wheelchair from day to day. It happens to thousands of Canadians every year following a spinal cord injury (SCI). The spinal cord is the highway by which information is transferred from the body to the brain and vice versa. After SCI, in addition to the harmful effects on neurons, oligodendrocytes die. The oligodendrocytes are those cells that produce what’s surrounding the neuron’s extensions and increase the speed of transmission of information through the production of myelin.
Goal
Steve Lacroix’s research team found that endogenous inflammatory mediators called interleukin (IL)-1α is released by microglia after a spinal cord injury (SCI) and induces inflammation as well as oligodendrocytes’ death. The team was thus interested in understanding how (IL)-1α causes its toxic effects on myelin after SCI and what are the consequences.
Methodology
Researchers first injected a recombinant form of IL-1α in the cerebrospinal fluid of mice to study its effects on intact spinal cord. Then, genetically modified mice were created to invalidate the IL-1α receptor, the IL-1R1, in cell populations specific to the spinal cord. IL-1α was then injected in mice and the spinal cords were observed using different microscopy methods to see how cells responds in the absence of IL-1R1 in oligodendrocytes, microglia, astrocytes or endothelial cells. Along with observing the effects of IL-1α on inflammation, cell activity and cell death in intact and injured spinal cord, studies of locomotor recovery post-SCI were performed.
Main findings
IL-1α administration to intact mice results in immune cell infiltration and spinal cord oligodendrocytes death, replicating some of the acute effects of SCI. Interestingly, dead oligodendrocytes were replaced within 3 to 5 days by new oligodendrocytes, which may be more capable of remyelination. IL-1α or IL-1R1 invalidated mice recover more rapidly and more efficiently their locomotor function after SCI. Having demonstrated detrimental effects of IL-1α/IL-1R1 signaling in the injured spinal cord, researchers therefore aimed to investigate the mechanism underlying inflammation and oligodendrocyte death. Using genetically modified mice, it was shown that IL-1α effects on oligodendrocyte death are indirect. This death is partially caused by astrocytes, which are transformed into cells with toxic effects under IL-1α’s influence. Indeed, these so-called toxic astrocytes release reactive chemicals called ‘reactive oxygen species’, which cause oligodendrocytes’ death. It is also mediated by endothelial cells forming the spinal neurovasculature. Indeed, once stimulated by IL-1α, endothelial cells allow neutrophil infiltration and neuroinflammation. In both cases, IL-1α receptor inactivation on the surface of astrocytes or endothelial cells greatly reduces oligodendrocytes’ death.
Take home message
SCI affect millions of otherwise healthy men and women’s lives, often without warning. It’s obviously impossible to completely prevent such accidents and the primary damage they cause. However, a better understanding of the mechanisms underlying nerve tissue loss in the hours and days following the so-called primary injury, could allow a better control of secondary damage and thus limit the loss of function. This work shows that the release of IL-1α after SCI stimulates astrocytes and endothelial cells to adopt toxic behaviors causing inflammation and oligodendrocyte death.
