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

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 retained within the chromatin fraction and is not released along with 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 and implanted into mice. Lysates from cells undergoing necrosis 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 Matrigel were 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 from the myeloid cells. Nuclear trafficking and differential release during necrosis vs. apoptosis demonstrate that inflammation by IL-1α is tightly controlled.hypoxia | necrosis | apoptosis | inflammation | alarmin

IL-33 is processed into mature bioactive forms by neutrophil elastase and cathepsin G

“…In support of this model, we have shown that IL-33 is constitutively expressed to high levels in the nuclei of endothelial and epithelial cells in normal human tissues (27) and that it can be released in the extracellular space after cellular damage (23). Neutrophils are rapidly recruited into injured tissues during infection or in the absence of infection during "sterile inflammation," following the release of major alarmin molecules such as IL-1α and HMGB1 (28)(29)(30)(31)(32). After activation, they rapidly release serine proteases from cytoplasmic granules into the extracellular space (33).…”

“…We have previously proposed (23,27) that IL-33 may function as an endogenous danger signal or alarmin, similar to IL-1α and HMGB1 (28)(29)(30)(31)(32), to alert the immune system of cell or tissue damage during trauma or infection. In support of this model, we have shown that IL-33 is constitutively expressed to high levels in the nuclei of endothelial and epithelial cells in normal human tissues (27) and that it can be released in the extracellular space after cellular damage (23).…”

“…Further analyses revealed that IL-33 is constitutively expressed to high levels in the nuclei of endothelial and epithelial cells in vivo (27) and that it can be released in the extracellular space after cellular damage (23,24). IL-33 was, thus, proposed (23,24,27) to function as an endogenous danger signal or alarmin, similar to IL-1α and high-mobility group box 1 protein (HMGB1) (28)(29)(30)(31)(32), to alert cells of the innate immune system of tissue damage during trauma or infection.…”

FAM19A4 is a novel cytokine ligand of formyl peptide receptor 1 (FPR1) and is able to promote the migration and phagocytosis of macrophages

“…Many intracellular cytokines, such as IL-1a and IL-33, are released upon cellular disintegration and serve as first-line alarmins to mediate signaling functions via their receptors on neighboring cells. 35,36 FAM19A4 is a potential alarmin that is initially induced during infections. Additionally, FAM19A4 was upregulated in the neuroendocrine CRI-G1 cell line upon mitochondrial and oxidative stress (GDS4014, GPL1355, 1378557_at) and in human brain endothelial cells in an in vitro model of cerebral malaria; 37 this further verifies that the expression of FAM19A4 is inducible in different tissues and cells.…”

Secreted IL‐1α promotes T‐cell activation and expansion of CD11b+Gr1+ cells in carbon tetrachloride‐induced liver injury in mice

“…Membrane IL-1α (ß23kDa) is thought to be immunostimulatory [11], while cytosolic proIL-1α controls homeostatic functions, such as gene expression and control of proliferation and differentiation [12]. IL-1α is not secreted and retained in cells during apoptosis process [13]. Necrosis-induced IL-1α activity is dependent on cell type and calpain cleavage.…”