Acute ischemic stroke as a model of immunometabolic maladaptation and acute sterile inflammation: from ischemia to resolution, repair, and rehabilitation

Abstract

Background. Despite substantial advances in reperfusion therapy, acute ischemic stroke (AIS) remains one of the leading causes of mortality and long-term disability worldwide. Restoration of cerebral blood flow does not always result in favorable functional outcomes, highlighting the critical contribution of secondary injury mechanisms. Ischemic brain injury is now recognized as the initiating event of acute sterile inflammation, whereas AIS commonly develops on the background of chronic immunometabolic maladaptation associated with metabolic syndrome, diabetes mellitus, atherosclerosis, and aging. Purpose – to summarize current evidence on the role of acute sterile inflammation in the pathogenesis of AIS, integrate the molecular, cellular, neuroendocrine, and immunometabolic mechanisms underlying ischemic and reperfusion injury, and outline promising directions for future therapeutic and rehabilitation strategies. Materials and Methods. A narrative review of contemporary experimental, clinical, and translational studies, systematic reviews, meta-analyses, and international guidelines addressing neuroinflammation, reperfusion injury, immunometabolic adaptation, inflammation resolution, and post-stroke recovery was performed. Results. Current evidence indicates that DAMP-mediated activation of innate immunity, neurovascular unit dysfunction, systemic immune responses, neuroendocrine regulation, and metabolic reprogramming constitute a coordinated phase-dependent adaptive response. The biological outcome largely depends on the timely transition from the effector phase of inflammation to its resolution, tissue repair, and neuroplasticity. This concept supports considering treatment and rehabilitation as interconnected stages of a continuous recovery process rather than separate therapeutic interventions. Conclusions. Acute ischemic stroke may be regarded as a clinical model of the sequential transition from chronic immunometabolic maladaptation to acute sterile inflammation, followed by inflammation resolution, tissue repair, and neuroplasticity. This integrative concept unifies current molecular, cellular, neuroendocrine, and immunometabolic perspectives and provides a pathophysiological framework for the development of personalized therapeutic and rehabilitation strategies.