Proposed mechanism of neuroinflammation in SCA. Sickle cells and inflammatory cells in the circulation release reactive oxygen species (ROS) and proinflammatory cytokines, including IL-1β, that lead to an inflamed, porous endothelium. Inflammatory cells extravasate into the extravascular space where they trigger an inflammatory response. Inflammation causes increased blood-brain barrier permeability and chronic deleterious activation of the microglia and astrocytes that leads to neuronal damage and central sensitization (left). Inflammatory cytokines also activate receptors in peripheral nerve terminals causing peripheral sensitization and hyperalgesia (right). Both central and peripheral sensitization are responsible for chronic pain in SCA. Professional illustration by Somersault18:24.