MASH-Associated T Cell Activation and Neuroinflammation: Evidence for a Hepatosystemic Immune Axis.

"The liver is the origin of the veins and the source of the blood."-De Usu Partium Galen.Galen's hepatocentric physiology foreshadowed the liver-brain axis, a network linking vagal signaling, cytokines, metabolites, and migratory immune cells. Central to the immune arm of this axis, the liver generates 25 to 50% of thoracic duct lymph, positioning hepatic lymphatic output as a significant, though not yet fully characterized, source of T cells and cytokines in systemic circulation, a contribution that increases with hepatic inflammation in chronic metabolic diseases. We propose that T lymphocytes are the key cellular effectors through which inflammation originating in the liver, propagating systemically, a process we term hepatosystemic inflammation, reaches the central nervous system (CNS). In metabolic dysfunction-associated steatotic liver disease, hepatosystemic inflammation generates peripheral "push signals" that may license T cells for CNS access, while neuroinflammatory "pull signals" at CNS barrier interfaces may establish permissive entry points. In conclusion, we propose that T cell licensing by hepatosystemic signals represents the immune arm of the liver-brain axis and a mechanistic bridge between metabolic liver disease and neuroimmune dysfunction and associated cognitive decline, and identifies candidate therapeutic targets along this cascade.