FIGURE 5.

Volume transmission as a vehicle of neuroimmune communication. Compounds in the extracellular spaces of the CNS are released from neurons, glia, axons (including varicosities), cell bodies and dendrites in addition to synaptic terminals (1). Among the most active, relevant compounds are neurotransmitters such as glutamate, cytokines (CKs), and chemokines (CMKs), all of which can influence cell activity depending on the local expression of receptors and transporters, and all of which can act on – and be released by – resident and itinerant leukocytes. The large volume of brain tissue exposed to so many sources of active compounds led to the concept of ‘volume transmission.’ The primary neuroactive substances promote CK release (2) while CK receptors can release neurotransmitters and related compounds (3). The cytokines can also directly modulate neuron and synaptic function, affecting excitability and plasticity. The major neuroactive kynurenine metabolites include kynurenic acid (glutamate antagonist) and quinolinic acid (NMDAR agonist). The extracellular compounds may act on leukocytes in the CNS which later re-enter the circulation and interact with peripheral leukocytes (4). Kynurenine can enter and leave cells relatively readily, acting as a paracrine agent to maintain or enhance levels in nearby cells.