Role of IL-1α in necrosis versus apoptosis. (1 left and right) In healthy cells of mesenchymal origin, the IL-1α precursor is found diffusely in the cytoplasm but also in the nucleus where it binds to chromatin. (2 right) During normal cell turnover, an apoptotic signal drives cytoplasmic IL-1α into the nucleus and is no longer a dynamic in the cell. The cell shrinks. (2 left) Cells exposed to hypoxia begin to die, and nuclear IL-1α moves out of the nucleus into the cytoplasm. Taking on water, the cell swells as the necrotic process begins. (3 left) As the necrotic process continues, there is loss of membrane integrity, and cytoplasmic contents containing the IL-1α precursor leak out. (3 right) Tissue macrophages take up the apoptotic cell into endocytotic vesicles. (4) In the vesicles, the apoptotic cell is digested, and there is no inflammatory response from the macrophage. (5 left) The IL-1α precursor is released into the extracellular compartment and binds to IL-1RI expressed on adjacent cells or to resident tissue macrophages. The tissue macrophage responds with synthesis of the IL-1β precursor as well as increased in caspase-1. From step 3 left, ATP is also released on cell death and activates the P2X7 receptor for activation of caspase-1. (6) Caspase-1 is activated by the inflammasome, cleaves the IL-1β precursor, and mature, active IL-1β is released. Alternatively, IL-1β is released via pyroptosis. (7) Once released, IL-1β induces chemokine production, resulting in a chemoattractant gradient. (8) As the endothelium of the microcirculation expresses adhesion molecule, blood neutrophils adhere and cross into the ischemic area. (9) With the infiltration of myeloid cells (monocytes and neutrophils), there is expanded inflammation, which extends beyond the initial area of ischemia.