The skull–meninges–brain axis: a new paradigm for systemic inflammation-driven encephalopathy

Despite the significant clinical burden of sepsis-associated encephalopathy (SAE), current models centering on blood-brain barrier (BBB) damage as the initiating event fail to fully explain the rapid neurocognitive deterioration. This review proposes a paradigm-shifting meningeal sentinel framework that repositions the meninges as the primary immunological gateway in SAE. We integrate three sequential stages – signal sensing, microenvironmental remodeling, and parenchymal propagation – into a unified model in which systemic inflammation is detected by meningeal border-associated immune compartments before overt BBB disruption. Central to this framework are the skull bone marrow–dura mater–brain axis enabling rapid myeloid cell delivery via transcortical channels, meningeal lymphatic dysfunction, and CD4 + T cell suppression, which collectively relay danger signals to the brain. This model reframes BBB breakdown as a downstream amplification event, offering a cohesive explanation for the early cognitive deficits in sepsis and distinguishing SAE from other neuroinflammatory disorders. Importantly, the framework predicts that meningeal-derived mediators enter the cerebrospinal fluid earlier than parenchymal injury markers, opening a window for early diagnosis. Targeting the skull–meninges–brain axis – through modulation of calvarial myelopoiesis, enhancement of lymphatic drainage, or restoration of meningeal T-cell function – offers strategies to prevent irreversible brain damage. This meninges-centered perspective thus advances mechanistic understanding and provides a template for systemic inflammation-driven encephalopathies.