Differential release of chromatin-bound IL-1α discriminates between necrotic and apoptotic cell death by the ability to induce sterile inflammation

Idan Cohen, Peleg Rider, Yaron Carmi, Alex Braiman, Shahar Dotan, Malka R. White, Elena Voronov, Michael U. Martin, Charles A. Dinarello, Ron N. Apte

Research output: Contribution to journalArticlepeer-review

Abstract

IL-1α, like IL-1β, possesses multiple inflammatory and immune properties. However, unlike IL-1β, the cytokine is present intracellularly in healthy tissues and is not actively secreted. Rather, IL-1α translocates to the nucleus and participates in transcription. Here we show that intracellular IL-1α is a chromatin-associated cytokine and highly dynamic in the nucleus of living cells. During apoptosis, IL-1α concentrates in dense nuclear foci, which markedly reduces its mobile nature. In apoptotic cells, IL-1α is retainedwithin the chromatin fraction and is not released alongwith the cytoplasmic contents. To simulate the in vivo inflammatory response to cells undergoing different mechanisms of death, lysates of cells were embedded in Matrigel plugs andimplantedintomice. Lysates fromcellsundergoingnecrosis recruited cells of the myeloid lineage into the Matrigel, whereas lysates of necrotic cells lacking IL-1α failed to recruit an infiltrate. In contrast, lysates of cells undergoing apoptotic death were inactive. Cells infiltrating the Matrigelwere due to low concentrations (20-50 pg) of the IL-1α precursor containing the receptor interacting C-terminal, whereas the N-terminal propiece containing the nuclear localization site failed to do so. When normal keratinocytes were subjected to hypoxia, the constitutive IL-1α precursor was released into the supernatant. Thus, after an ischemic event, the IL-1α precursor is released by hypoxic cells and incites an inflammatory response by recruiting myeloid cells into the area. Tissues surrounding the necrotic site also sustain damage fromthe myeloid cells. Nuclear trafficking and differential release during necrosis vs. apoptosis demonstrate that inflammation by IL-1α is tightly controlled.

Original languageEnglish
Pages (from-to)2574-2579
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number6
DOIs
StatePublished - 9 Feb 2010
Externally publishedYes

Keywords

  • Alarmin
  • Apoptosis
  • Hypoxia
  • Inflammation
  • Necrosis

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