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 from dead cells. Sterile inflammation worsens 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 oxygen‐glucose 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.