Interleukin-1 in Stroke: From Bench to Bedside.

Inflammation is a host defense response to infection that normally culminates in pathogen removal and tissue repair. In the absence of a pathogen, sterile inflammation occurs, which is now recognized as a major contributor to noncommunicable disease (ie, cardiovascular diseases, cancers, chronic respiratory diseases, and diabetes mellitus). Although several regulatory molecules are implicated in inflammation, a key central role is provided by members of the interleukin-1 (IL-1) family, important mediators of the innate immune response.1 Here, we provide an overview of the basic biology of IL-1, before going on to describe both the preclinical and the clinical evidence that suggest IL-1 to be a major therapeutic target in all forms of stroke, including details of completed and ongoing clinical trials. It should be noted that in compiling this review, a full systematic search strategy was not used and that any negative data are likely limited by publication bias. Although 11 members of the IL-1 family have been described, the most important of these and most studied in the context of stroke are the agonists IL-1α and IL-1β, and the IL-1 receptor antagonist (IL-1Ra).2 Both IL-1α and IL-1β are created as 31-kDa precursor proteins that undergo enzymatic cleavage to bioactive 17-kDa forms,3 although they differ in that pro–IL-1α possesses some biological activity, whereas pro–IL-1β is completely inactive.4 Cleavage of IL-1β is classically achieved via caspase-1 (or IL-1–converting enzyme), activity of which is triggered via the activation of the inflammasome, an intracellular protein complex.5 Inflammasome activation in sterile inflammation is triggered by damage-associated molecular patterns, which are released by necrotic cells within the ischemic brain.1 Pro–IL-1β can also be cleaved to the active 17-kDa form by the action of neutrophil serine proteases, including proteinase 3 and elastase.4 Given the contribution of neutrophils to ischemic brain …