Peripheral and central cytokines and neuroimmune circuits
Cytokines mediate signaling among immune cells. They activate or inhibit other immune cells, which results in a complicated circuit. Cytokines act on cell membrane receptors like neurotransmitters or on intracellular receptors like hormones to transmit information to cells. They are mainly secreted from monocytes (or macrophages) or lymphocytes as well as from brain cells, such as neurons, endothelial cells, astrocytes, and microglia. Cytokines are divided into various types, including interleukins (ILs), chemokines, tumor necrosis factors (TNFs), interferons (IFNs), and transforming growth factors (TGFs).
Proinflammatory cytokines include IL-1, IL-2, IL-6, IFN-γ, and TNF-α. Anti-inflammatory cytokines include IL-4, IL-10, IL-11, IL-13, and TGF-β. The proinflammatory cytokines activate cyclo-oxygenase-2 (COX-2), increase the levels of prostaglandin E2 (PGE2), activate inflammatory cells, and induce inflammatory reactions. They interact with each other to maintain balance. For example, IL-10 reduces TNF production, and the IL-1 receptor antagonist (IL-1ra) antagonizes the IL-1 receptor. In chronic inflammation, the proinflammatory cytokines are increased and the anti-inflammatory cytokines are decreased, which results in the onset of various diseases.
The production of the peripheral cytokines that are secreted from monocytes or macrophages is determined by the level of immune activity. In pathologic states, such as acute or chronic inflammation or tissue damage, immune function and macrophages are activated to increase the levels of proinflammatory cytokines. Cortisol secreted from the adrenal cortex as a result of HPA-axis activation is most important in peripheral cytokine production. When cortisol levels are low, the production of proinflammatory cytokines increases, while their production is inhibited when cortisol levels are high. Neurotransmitters regulate peripheral cytokines through cortisol levels. For example, acetylcholine (Ach), dopamine (DA), and noradrenaline (NA) promote the secretion of corticotropin-releasing hormone (CRH) in the hypothalamus, and serotonin (5-HT) inhibits the secretion of CRH in the hypothalamus and adrenocorticotropic hormone (ACTH) in the pituitary. In addition, the autonomic nervous system regulates peripheral cytokine production. Parasympathetic nerves directly affect the immune system, while sympathetic nerves affect the immune system through NA secretion from the peripheral sympathetic ganglia. The vagus nucleus, which is located in the pons, inhibits immune functions and cytokine production through the secretion of Ach from the vagus nerve (Figure 1).
Figure 1 The role of cytokine network in depression in connection with immune system, hypothalamic-pituitary-adrenal axis, neurotransmitter, and autonomic nerve system.
The figure shows communication between peripheral and central cytokine system. Early innate proinflammatory cytokines released by macrophage (TNF-α, IL-1, IL-6 and INF-α), and late acquired T cell cytokines (IL-2 and INF-γ) stimulate glucocorticoid secretion by acting at all three levels of the HPA axis. Glucocorticoids are negatively feedback on the peripheral immune system to suppress the production of proinflammatory cytokines. Glucocorticoids also play an important role in causing a shift from cellular (T-helper 1) to humoral (T-helper 2) immune responses. The central cytokines are usually secreted from the astrocyte or microglia. Central cytokines (IL-1, IL-6, TNF-α, and IFN-γ) are considered to be involved in neuroplasticity in brain. The neurotransmitters (NA, ACH, and 5-HT) regulate the peripheral cytokines by changing the cortisol concentration level. The Ach, DA, and NA promote the secretion of the CRH in hypothalamus, and 5-HT inhibits the secretion of the CRH in hypothalamus and the ACTH in pituitary. The ANS also regulates the peripheral cytokine production. The parasympathetic nerve directly reaches the immune system while the sympathetic nerve affects the immune system through the NA secretion from the peripheral sympathetic ganglia. 5-HT: Serotonin; ACH: Acetylcholine; ACTH: Adrenocorticotropic hormone; ANS: Autonomic nerve system; CRH: Corticotropin-releasing factor; DA: Dopamine; HPA: Hypothalamic-pituitary-adrenal; NA: Noradrenalin; PVN: Paraventricular nucleus of the hypothalamus; TH: Helper T cell; IL: Interleukins; TNF: Tumor necrosis factor; IFN: Interferons.
Because peripheral cytokines are hydrophilic and have large molecular weights, they are unable to pass through the blood-brain barrier (BBB) in their normal state. However, they can pass through the BBB in pathological states that involve increased BBB permeability. Moreover, cytokines are also able to affect the CNS through mediators, such as nitric oxide or prostaglandins released in response to cytokines[9,10]. IL-1 receptors are densely distributed in glial cells near arterioles or the plexus choroideus. This suggests that the IL-1 receptors in the CNS and IL-1 in the peripheral blood actively communicate with each other. Additional channels through which peripheral cytokines transmit immune signals to the CNS include passive diffusion through the circumventricular organs (brain regions that do not have a BBB), active transport to the CNS, and nerve conduction pathways through the vagus nerve.
Central cytokines are usually secreted from astrocytes or microglia, but neurons can secrete them in certain conditions. Central cytokines are produced in a number of brain regions, including the circumventricular region, hypothalamus, hippocampus, cerebellum, forebrain, basal ganglia, and brain stem nuclei. IL-1, which is secreted from the brain, is found in the hypothalamus and hippocampus. The roles of central cytokines in the brain are not fully understood. However, the proinflammatory cytokines IL-1, IL-6, TNF-α, and IFN-γ have been implicated in neuronal development, neuroplasticity, synaptogenesis, and tissue repair. Proinflammatory cytokines promote neuronal necrosis after traumatic brain injuries.
Cytokine receptors are located in the immune system and various tissues, including the peripheral nervous system and CNS. For example, IL-1, IL-2, IL-6, and TNF-α receptors are densely distributed in the hippocampus and hypothalamus. IL-1 has two receptor types: Type I and type II. The nuclear transcription factor nuclear factor kappa B (NFκB) is activated and intracellular signals can be transmitted through the type I receptor. A role of cytokines in specific mental functions and/or mental diseases has been suggested because of the locations of their receptors in the CNS and not because of the specific functions of the cytokines. The important CNS structures that are affected by central cytokines include the locus coeruleus, hippocampus, prefrontal cortex, and hypothalamus. These CNS structures are associated with the biological processes that underlie psychological changes.