The alarmin interleukin-1α triggers secondary degeneration through reactive astrocytes and endothelium after spinal cord injury

Nature Communications, 2022 · DOI: 10.1038/s41467-022-33463-x · Published: October 4, 2022

Simple Explanation

Spinal cord injury (SCI) causes inflammation, leading to further damage and death of certain brain cells. This study found that a molecule called interleukin (IL)-1α, released by damaged brain immune cells after SCI, starts a harmful chain reaction. IL-1α causes the death of oligodendrocytes (OLs), cells important for nerve insulation, through the activation of other brain cells: astrocytes and endothelial cells. Blocking IL-1α or molecules it triggers could protect OLs after SCI. Microglia also appear to protect OLs by sequestering IL-1 cytokines within the extracellular compartment through the decoy IL-1R2.

Study Duration

Not specified

Participants

Mice

Evidence Level

Not specified

Key Findings

1
Microglia-derived IL-1α induces OL death through the astrocytic and endothelial IL-1R1.
2
Stimulation of astrocytic IL-1R1 by IL-1α converted these cells into a reactive phenotype characterized by enhanced production and release of reactive oxygen species (ROS) inciting toxicity in OLs.
3
Blocking ROS production in IL-1α-injected mice and SCI mice prevented OL death.

Research Summary

The study investigates the role of the alarmin IL-1α in spinal cord injury (SCI). IL-1α, primarily derived from damaged microglia, triggers a cascade of events leading to oligodendrocyte (OL) death, involving astrocytes and endothelial cells. Blocking IL-1α signaling or reactive oxygen species (ROS) production may offer a therapeutic avenue to prevent OL loss after SCI.

Practical Implications

Therapeutic Target

IL-1α and its downstream signaling pathways, particularly ROS production, are potential therapeutic targets for reducing secondary degeneration after SCI.

Cell-Specific Targeting

Targeting IL-1R1 in astrocytes and endothelial cells, rather than microglia, may be a more effective strategy for neuroprotection after SCI.

Combination Therapy

Combining IL-1α inhibition with antioxidant treatments may provide synergistic benefits in preventing OL loss and improving functional outcomes after SCI.

Study Limitations

1
Cre-reporter mouse lines have some limitations, the most important being that recombination in a speciﬁc cell type is often incomplete.
2
The administration of a single dose of this cytokine is not enough to replicate the chronicity and complexity of inﬂammation and the physical outcomes present in SCI.
3
Our ﬁndings regarding the effects of IL-1α likely apply to the ﬁrst 24 h after the injury, when the cytokine is present.

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