Delirium is an acute neurocognitive disorder frequently triggered by systemic inflammation and characterized by abrupt disturbances in attention and memory. Although common in acute illness, trauma, and surgery, the mechanisms linking peripheral inflammation to rapid cognitive disruption remain poorly understood. Growing evidence suggests that inflammatory cytokines and chemokines circulating in the bloodstream activate the choroid plexus, and when stimulated, the barrier tissue produces chemokines that compromise tight-junction integrity, alter cerebrospinal fluid composition, and influence neural circuits involved in cognitive function. Chemokines such as eotaxins and the CCL3/CCL4/CCL5 families, along with their receptors, CCR3 and CCR5, emerge as particularly relevant because their signaling profiles mirror patterns associated with barrier leakiness and cognitive impairment during inflammatory stress.
CCR3 and CCR5 are chemokine receptors that regulate immune activation, barrier stability, and neuronal signaling. Activation of these receptors can amplify inflammatory cascades, destabilise barrier structures, and suppress neuronal plasticity processes, thereby heightening susceptibility to cognitive deficits. As systemic inflammation induces chemokine production at the choroid plexus, enhanced signaling through CCR3 and CCR5 may represent a shared inflammatory pathway that acutely destabilises the blood-cerebrospinal fluid barrier (BCSFB) and contributes to delirium associated cognitive impairment.
The aim of this project is to investigate whether chemokine signaling through CCR3 and CCR5 at the choroid plexus links systemic inflammation to barrier disruption and to exacerbate neuroinflammation and to evaluate whether these patterns are replicate in humans experiencing delirium. Specifically, I hypothesise that the activation of CCR3 and CCR5 during systemic inflammation drives chemokine responses in the choroid plexus that disrupt barrier integrity, and antagonism of these receptors will attenuate these effects. Objectives include measuring chemokine and chemokine receptor expression in existing choroid plexus RNA samples (i.e. already collected), mapping the distribution of chemokine signaling in brain sections and reconciling these observations with chemokine measurements in human CSF samples.