Contemplating IL‐6, a double‐edged sword cytokine: Which side to use for stroke pathology?

Interleukin (IL)‐6 is a unique cytokine due to its dual signaling, with one pathway being pro‐inflammatory (trans) and the other homeostatic (classical). Both of these pathways have been implicated in neuroinflammation following stroke, with initial inflammatory mechanisms being protective and later anti‐inflammatory signaling promoting ischemic tissue recovery. IL‐6 plays a major role in stroke pathology. However, given these distinctive IL‐6 signaling consequences, IL‐6 is a difficult cytokine to target for stroke therapies. Recent research suggests that the ratio between the pro‐inflammatory binary IL6:sIL6R complex and the inactive ternary IL6:sIL6R:sgp130 complex may be a novel way to measure IL‐6 signaling at different time points following ischemic injury. This ratio may approximate functional consequences on individualized stroke therapies, allowing clinicians to determine whether IL‐6 agonists or antagonists should be used at specific time points.