Nuclear retention of IL-1α 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 fromdead cells. Sterile inflammationworsens damage in a number of injury paradigms. The pro-inflammatory cytokine IL-1α 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-1α is produced by microglia, the resident brain macrophages. We found that IL-1α is actively trafficked to the nuclei of microglia, and hence tested the hypothesis that trafficking of IL-1α to the nucleus would inhibit its release following necrotic cell death, limiting sterile inflammation. Microglia subjected to oxygenglucose deprivation died via necrosis. Under these conditions, microglia expressing nuclear IL-1α released significantly less IL-1α than microglia with predominantly cytosolic IL-1α. The remaining IL-1α was immobilized in the nuclei of the dead cells. Thus, nuclear retention of IL-1α may serve to limit inflammation following cell death. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA.