Nuclear retention of IL-1 alpha by necrotic cells: a mechanism to dampen sterile inflammation.
Sterile inflammation is a host response to tissue injury that is mediated by damage-associated molecular patterns released from dead cells. Sterile inflammation worsens damage in a number of injury paradigms. The pro-inflammatory cytokine IL-1 alpha is reported to be a damage-associated molecular pattern released from dead cells, and it is known to exacerbate brain injury caused by stroke. In the brain, IL-1 alpha is produced by microglia, the resident brain macrophages. We found that IL-1 alpha is actively trafficked to the nuclei of microglia, and hence tested the hypothesis that trafficking of IL-1 alpha to the nucleus would inhibit its release following necrotic cell death, limiting sterile inflammation. Microglia subjected to oxygen-glucose deprivation died via necrosis. Under these conditions, microglia expressing nuclear IL-1 alpha released significantly less IL-1 alpha than microglia with predominantly cytosolic IL-1 alpha. The remaining IL-1 alpha was immobilized in the nuclei of the dead cells. Thus, nuclear retention of IL-1 alpha may serve to limit inflammation following cell death.
Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester, UK.
Nadia M
NM
Luheshi
Barry W
BW
McColl
David
D
Brough
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D053582:Interleukin-1alpha / Q000378:metabolism*; D017628:Microglia / Q000378:metabolism; D009336:Necrosis / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology
D053582:Interleukin-1alpha