Figure 1

Initiation of sterile inflammation by IL-1α following an ischemic event. ①, In the necrotic area, dying cells lose membrane integrity. ②, Dying cells release their contents including the IL-1α precursor. Anti-IL-1α antibodies neutralize IL-1α at this step. ③,IL-1α binds to IL-1R type I (IL-1RI) on nearby resident fibroblasts, epithelial cells or in the brain astrocytes, releasing chemokines and establishing a chemokine gradient. Anakinra or anti-IL-1RI prevents this step. The chemokine gradient facilitates the passage to blood neutrophils into the ischemic area. ④, Capillaries in the ischemic tissues express the intra-cellular adhesion molecule-1 (ICAM-1). Circulating blood neutrophils roll on the endothelium, adhere to ICAM-1 and enter the ischemic tissue via diapedesis. ⑤, The number of neutrophils increases into the area of the necrotic event; the presence of local IL-1 prolongs the survival of neutrophils at this step. ⑥, Neutrophil proteases cleave the extracellular IL-1α precursor into mature, more active forms. ⑦, Neutrophils scavenge dying cells and release proteases that contribute to the destruction of penumbral cells. Image reproduced (no permission needed) from Dinarello et al. (137): Charles A Dinarello, Anna Simon, Jos W M van der Meer. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nature Reviews Drug Discovery. 2012;11:633-52.