Towards a Cortical Framework of Neuroimmune Representation: The Insular Cortex at the Brain-Immune Interface

For a long time, the immune system was considered as an autonomous defense network. The possibility that its functional states are actively represented and regulated at the cortical level challenges this dogma and demands a reconceptualization of immunity as a brain-orchestrated process. Especially, the insular cortex is uniquely positioned to represent internal physiological states and to exert top-down control over peripheral immune responses. Within the insular cortex, interoceptive stimuli are transformed into integrated representations of bodily states. Through projections to the hypothalamus and the brainstem, the insular cortex influences autonomic and neuroendocrine outputs, enable context-dependent modulation of systemic cytokine production and immune cell activity. Importantly, recent findings suggest that previous immune experiences are not only stored as neuronal engrams within insular cortical circuits but can also be reinstated upon selective reactivation. This perspective discusses the role of the insular cortex as a central hub within a dynamic, network linking interoceptive and cortical processes with immunity.

Beyond its role in bidirectional neuroimmune regulation, the insular cortex has been proposed to function as a cortical hub for encoding immune-state representations.

Resolving where and how the brain encodes peripheral immune states will not only illuminate how central dysregulation contributes to disease, but may reveal new therapeutic targets in which experiential and cognitive variables become tractable levers for immune intervention.