Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases

Abstract

Interleukin-1 (IL-1) is a highly active pro-inflammatory cytokine that lowers pain thresholds and damages tissues. Monotherapy blocking IL-1 activity in autoinflammatory syndromes results in a rapid and sustained reduction in disease severity, including reversal of inflammation-mediated loss of sight, hearing and organ function. This approach can therefore be effective in treating common conditions such as post-infarction heart failure, and trials targeting a broad spectrum of new indications are underway. So far, three IL-1-targeted agents have been approved: the IL-1 receptor antagonist anakinra, the soluble decoy receptor rilonacept and the neutralizing monoclonal anti-IL-1β antibody canakinumab. In addition, a monoclonal antibody directed against the IL-1 receptor and a neutralizing anti-IL-1α antibody are in clinical trials.

Figure 1. Initiation of sterile inflammation by IL-1α following an ischaemic event

Step 1: in the necrotic area, dying cells lose membrane integrity. Step 2: dying cells release their contents, including the interleukin-1α (IL-1α) precursor. Anti-IL-1α antibodies neutralize IL-1α at this step. Step 3: IL-1α binds to IL-1 receptor type I (IL-1RI) on nearby resident fibroblasts, epithelial cells or in brain astrocytes, releasing chemokines and establishing a chemokine gradient. Anakinra or anti-IL-1RI antibodies block this step. The chemokine gradient facilitates the passage of blood neutrophils into the ischaemic area. Step 4: capillaries in the ischaemic tissues express intercellular adhesion molecule 1 (ICAM1). Circulating blood neutrophils roll on the endothelium, adhere to ICAM1 and enter the ischaemic tissue via diapedesis. Step 5: the number of neutrophils in the area of the necrotic event increases; the presence of local IL-1 prolongs the survival of neutrophils at this step. Step 6: neutrophil proteases cleave the extracellular IL-1α precursor into mature, more active forms. Step 7: neutrophils scavenge dying cells and release proteases that contribute to the destruction of penumbral cells.

Figure 2. Role of IL-1 β in sterile inflammation

Step 1: following an ischaemic event, cells undergo hypoxic damage, lose membrane integrity and the dying cell releases cell contents (see FIG. 1). Step 2: the preformed interleukin-1α (IL-1α) precursor is released. Anti-IL-1α antibodies neutralize IL-1α at this step. 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. Step 4: triggered by the binding of IL-1α to IL-1RI, resident macrophages synthesize inflammatory genes as well as the IL-1β precursor. Step 5: the IL-1β precursor undergoes intracellular processing by caspase 1. Caspase 1 inhibitors prevent the processing of IL-1β at this step. Step 6 involves the secretion of active IL-1β. Rilonacept or antibodies of IL-1β neutralize IL-1β in the extracellular compartment at this step. Step 7: with the breakdown of vascular integrity in the necrotic area, IL-1β gains access to the vascular compartment. Step 8: IL-1β binds to IL-1RI on capillaries and induces vascular cell adhesion molecule 1 (VCAM1). Step 9: blood monocytes roll along the endothelium and bind to VCAM1, followed by their migration into the ischaemic tissue via diapedesis. Increasing numbers of monocytes become a source of increased production of IL-1β. Step 10: opening of the endothelial junction results in capillary leak, with the passage of plasma proteins into the ischaemic area. Step 11: platelet-derived IL-1α binds to the endothelial IL-1RI and induces the expression of intercellular adhesion molecule 1 (ICAM1). Step 12: large numbers of neutrophils enter the tissue space and the presence of local IL-1 prolongs the survival of neutrophils. Step 13: neutrophil proteases are released. Step 14: the IL-1β precursor released into the extracellular space is cleaved by serine proteases to generate active IL-1β. Natural inhibitors of serine proteases such as α1 antitrypsin prevent the extracellular processing of the IL-1β precursor. Step 15: increasing numbers of neutrophils surround the necrotic area, scavenging dead cells and debris. Damaging neutrophilic proteases attack and injure penumbral cells, resulting in increased loss of function of the organ undergoing the ischaemic event. Blocking IL-1 cannot restore the necrotic tissue but reduces the loss of penumbral cells.

Timeline

IL-1-blocking agents in various disease states The timeline highlights the testing of interleukin-1 (IL-1)-blocking agents in various but not all indications. AOSD, adult-onset Still’s disease; CANTOS, Canakinumab Anti-inflammatory Thrombosis Outcome Study; CAPS, cryopyrin-associated periodic syndrome; FMF, familial Mediterranean fever; HIDS, hyper-IgD syndrome; MWS, Muckle–Wells syndrome; SJIA, systemic juvenile idiopathic arthritis; STEMI, ST segment elevation myocardial infarction; TRAPS, TNF receptor-associated periodic syndrome.