Defective efferocytosis in intracranial aneurysms: linking non-resolving inflammation to maladaptive wall remodeling

Intracranial aneurysm are acquired dilatations of cerebral arteries that may rupture and cause subarachnoid hemorrhage. Their progression involves hemodynamic stress, endothelial dysfunction, chronic inflammation, smooth muscle cell loss, extracellular matrix degradation, and maladaptive repair. Although inflammatory activation has been widely studied, the failure of inflammation resolution remains poorly understood. Efferocytosis, the clearance of apoptotic cells by macrophages and neighboring cells, is essential for resolving inflammation and maintaining tissue homeostasis. When efferocytosis is impaired, apoptotic cells undergo secondary necrosis, releasing damage-associated signals that sustain inflammation. In intracranial aneurysms, oxidative stress, hypoxia, protease activation, intraluminal thrombus, inflammatory cytokines, macrophage dysfunction, HMGB1, MerTK cleavage, and reduced bridging molecules such as Gas6, Protein S, and MFG-E8 may compromise efferocytosis. Failed apoptotic cell clearance may amplify inflammasome activation, matrix degradation, smooth muscle cell depletion, and wall fragility. This review highlights efferocytosis failure as a potential mechanism linking unresolved inflammation to aneurysm progression and rupture, and discusses related biomarkers and therapeutic opportunities.