Figure 2

Role of IL 1β in sterile inflammation. ①, Following an ischemic event, cells undergo hypoxic damage, lose membrane integrity, and the dying cell releases cell content (see Figure 1). ②, The preformed IL-1α precursor is released. Anti-IL-1α antibodies neutralize IL-1α at this step. ③, IL-1α binds to IL-1 receptor type I (IL-1RI) on nearby resident macrophages. Anakinra or anti-IL-1RI antibodies prevent IL-1α activity at this step. ④, Triggered by IL-1α binding to the IL-1RI, resident macrophages synthesize inflammatory genes as well as the IL-1β precursor. ⑤, Intracellular processing of the IL-1β precursor by caspase-1. Caspase-1 inhibitors prevent the processing of IL-1β. ⑥, Active secretion of active IL-1β. Antibodies to IL-1β or rilonacept neutralize IL-1β in the extracellular compartment at this step. ⑦, With breakdown of the vascular integrity in the necrotic area, IL-1β gains access to the vascular compartment. ⑧, IL-1β binds to IL-1RI on capillaries and induces vascular cell adhesion molecule-1 (VCAM-1). ⑨, Blood monocytes roll along the endothelium and bind to VCAM-1, followed by emigration into the ischemic tissue via diapedesis. Increasing numbers of monocytes become a source of greater production of IL-1β. ⑩, Opening of the endothelial junction resulting in capillary leak with the passage of plasma proteins into the ischemic area. ⑪, Platelet-derived IL-1α binds to the endothelial IL-1RI and induces ICAM-1. ⑫, Large numbers of neutrophils enter the tissue space, and the presence of local IL-1 prolongs the survival of neutrophils. ⑬, Release of neutrophil proteases. ⑭, IL-1β precursor released into the extracellular space is cleaved by serine proteases generating active IL-1β. Natural inhibitors of serine proteases such as a₁-antitrypsin prevent the extracellular processing of the IL-1β precursor. ⑮, Increasing numbers of neutrophils surround the necrotic area, scavenging dead cells and debris. ⑯, Damaging neutrophilic proteases attack and injure penumbral cells, increasing the loss of function. Blocking IL-1 cannot restore the necrotic tissue but reduces the loss of the penumbral cells. Image modified (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.