FIGURE 4.

An overview of neuroimmune communication. Routes of communication between the CNS and immune systems including the blood-brain barrier. (A) IDO1 expressed in microglia produces kynurenic acid and quinolinic acid, a selective agonist on cellular NMDARs. Astrocytes produces only kynurenic acid which blocks receptors for endogenous glutamate on neurons, glia, and leukocytes, while glia and leukocytes resident in or passing through the CNS (‘itinerant’ cells) produce a variety of neuroactive cytokines and other inflammatory mediators which modulate glial activity and neuron excitability. (B) Kynurenine and 3HK generated in the CNS or in peripheral tissues cross the blood-brain barrier in both directions partly by diffusion and partly by the active Large Neutral Amino Acid Transporter (LAT-1). Larger immune mediator molecules gain access to the CNS by diffusion in areas of higher permeability (a), although some mediators may be excluded by persistent efflux transporters (b) and several have dedicated active transporters (c). Alternatively, immune mediators can be secreted by leukocytes which have crossed the cerebrovascular endothelium (d). (C) In all compartments the cytokines can regulate kynurenine pathway enzymes, partly via the balance of pro-inflammatory and anti-inflammatory interleukins. In the immune system kynurenine initiates a feedback generation of IDO and more kynurenine via Aryl Hydrocarbon Receptors. The kynurenine generated determines the expression of FoxP3 and RORγt and thus CD4 + differentiation to Treg or inflammatory T cells. (D) Leukocyte receptors for immune system mediators and neuroactive compounds produced by neurons and glia, emphasizing their susceptibility to ligands produced by cells of the immune system and the peripheral and central nervous systems.