Blocking interleukin-1β in acute and chronic autoinflammatory diseases

Abstract

An expanding spectrum of acute and chronic inflammatory diseases is considered 'autoinflammatory' diseases. This review considers autoinflammatory diseases as being distinct from 'autoimmune' diseases. Autoimmune diseases are associated with dysfunctional T cells and treated with 'biologicals', including antitumour necrosis factorα, CTLA-Ig, anti-IL-12/23, anti-CD20, anti-IL-17 and anti-IL-6 receptor. In contrast, autoinflammatory diseases are uniquely attributed to a dysfunctional monocyte caspase 1 activity and secretion of IL-1β; indeed, blocking IL-1β results in a rapid and sustained reduction in the severity of most autoinflammatory diseases. Flares of gout, type 2 diabetes, heart failure and smouldering multiple myeloma are examples of seemingly unrelated diseases, which are uniquely responsive to IL 1β neutralization.

Figure 1. IL-1-mediated Autoinflammation

1. Myeloid lineage cells expressing IL-1RI bind either IL-1α or IL-1β. 2. The Toll-IL-1-Receptor (TIR) domains of the IL-1RI-IL-1R Accessory Protein complex recruit MyD88 and initiate signal transduction. 3. Following NFκB or AP-1 translocation to the nucleus, the IL-1β precursor is synthesized. 4. Oligomerization of components of the NLRP3 inflammasome with procaspase-1 [36]. 5. Activation of caspase-1. 6. Cleavage of the IL-1β precursor by caspase-1. 7. Release of active IL-1β into the extracellular space [, –95]. 8. Once released, IL-1β can bind to IL-1RI on non-myeloid cells such as endothelial and mesenchymal cells and stimulate the production of other cytokines and chemokines as well as mediators of inflammation, for example, COX-2, inducible nitric oxide and phospholipase A2. In addition, increases adhesion molecules, facilitating the emigration of inflammatory cells into injured or infected tissues. 9. On myeloid cells expressing IL-1RI, IL-1β activates the receptor and generates a signal resulting in more IL-1β [31]. Therapeutically, the cycle of IL-1-induced IL-1 is specifically arrested by reducing the activity of IL-1β via IL-1RI blockade (anakinra), binding of IL-1 to soluble IL-1 receptors (rilonacept) or neutralization by monoclonal anti-IL-1β antibodies (canakinumab, Xoma 052). Naturally, the cycle of IL-1-induced IL-1 can be controlled by endogenous IL-1Ra or endogenous IL-1RI type II.

Figure 2. IL-1β-mediated loss of the insulin-producing beta-cell in Type-2 diabetes

The islet receives its blood supply from a highly fenestrated vascular bed. Glucose, FFA and IL-1β itself as well as other cytokines enter the islet. In Type-2 diabetes, the islet contains increased numbers of macrophages, which produce chemokines and IL-1β itself as well as IL-1Ra. Macrophage IL-1β and macrophage IL-1Ra compete for occupancy of the IL-1RI on the beta-cell. In Type-2 diabetes, a low production of endogeneous IL-1Ra may contribute to beta-cell death. IL-1β, glucose and FFA enter the islet and directly stimulate beta-cell IL-1β production, which is toxic for the beta-cells. With time, beta-cell mass decreases and exogenous insulin is required. Arresting the cycle of IL-1β-induced IL-1β may restore dysfunctional beta-cells as well as arrest the loss of beta-cells.

Figure 3. Time-line for a role of IL-1β in heart failure

Top. Left to right. The pathogenesis of atherosclerosis is affected by IL-1β production by oxidized LDL and cholesterol crystals as demonstrated in human monocytes. In animal studies, high fat diets, lipid laden foam cells and FFA from adipocytes have demonstrated a role for IL-1β. In animal models as well as in humans, IL-1β contributes to the loss of insulin-production beta-cells resulting in hyperglycemia and endothelial cell damage. Bottom. Left to right. The atherosclerotic plaque is at risk for rupture via IL-1β-induced matrix metalloproteases. Once the integrity of the plaque surface in lost, platelets initiate clot formation. IL-1β is released from activated platelets and contributes to the inflammation of the plaque via increased chemokines and inflammatory cells[96]. During the ischemia of the infracted myocardium, IL-1β induces myocyte cell death via a caspase-1 mechanism. With loss of myocytes, there is loss of function clinically termed heart failure. In patients surviving ST-elevated myocardial infarction (STEMI), administration of anakinra for 14 days improved myocardial function compared to placebo-treated patients [71]