From inflammation to sickness and depression: when the immune system subjugates the brain

Abstract

In response to a peripheral infection, innate immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness behaviour. When activation of the peripheral immune system continues unabated, such as during systemic infections, cancer or autoimmune diseases, the ensuing immune signalling to the brain can lead to an exacerbation of sickness and the development of symptoms of depression in vulnerable individuals. These phenomena might account for the increased prevalence of clinical depression in physically ill people. Inflammation is therefore an important biological event that might increase the risk of major depressive episodes, much like the more traditional psychosocial factors.

Figure 1. Pathways that transduce immune signals from the periphery to the brain

The brain and the immune system communicate through different pathways. a | In the neural pathway, peripherally produced pathogen-associated molecular patterns (PAMPs) and cytokines activate primary afferent nerves, such as the vagal nerves during abdominal and visceral infections, and the trigeminal nerves during oro-lingual infections. Vagal afferents project to the nucleus tractus solitarius (NTS), and from there to the parabrachial nucleus (PB), the ventrolateral medulla (VLM), the hypothalamic paraventricular and supraoptic nuclei (PVN, SON), the central amygdala (CEA) and the bed nucleus of the stria terminalis (BNST). These last two structures form part of the extended amygdala, which projects to the periaqueductal grey (PAG). b | The humoral pathway involves circulating PAMPs that reach the brain at the level of the choroid plexus (CP) and the circumventricular organs, including the median eminence (ME), organum vasculosum of the laminae terminalis (OVLT), area postrema (AP) and suprafornical organ (SFO). In the circumventricular organs, PAMPs induce the production and release of pro-inflammatory cytokines by macrophage-like cells expressing Toll-like receptors (TLRs). As the circumventricular organs lie outside the blood–brain barrier (BBB), these cytokines still need to reach the brain. They do so by mechanisms that are still unknown, but involve volume diffusion.

Figure 2. Increased brain cytokine signalling impairs learning and memory

Studies in animals have demonstrated that acute activation of pro-inflammatory cytokine signalling in the brain in response to peripheral immune activation is associated with deficits in hippocampal-dependent memory such as contextual fear conditioning (a). Rats treated with lipopolysaccharide (LPS) shortly after exposure to an inescapable electric shock show less ‘freezing’ when re-exposed to the cage in which they were previously shocked. However, they still freeze in response to a tone that was previously paired with electric shocks, a phenomenon that is known as auditory-cued fear conditioning and is dependent on the amygdala (b). These behavioural data are consistent with the impairing effect of enhanced cytokine signalling on hippocampal long-term potentiation. In terms of information processing, information about stimulus contingencies and behavioural response outcomes is briefly processed by sensory memory. When attended to, this information is given cognitive meaning in the working memory register before being stored in the long-term memory register (c). The cognitive load theory capitalizes on the limited capacity of working memory to handle several pieces of information at the same time. This is not a problem in normal conditions as only a small amount of information needs to be processed by the working memory register. However, the intruding interoceptive sensations of sickness, which are mediated by pro-inflammatory cytokines during an episode of inflammation, are likely to increase the load on working memory and limit the ability to extract information about the temporal contingencies between nociceptive stimuli and exteroceptive environmental stimuli, especially when the exteroceptive stimuli lack salience (that is, diffuse contextual cues versus distinct auditory cues).

Figure 3. LPS-increased depression-like behaviour in mice

Peripheral administration of lipopolysaccharide (LPS) induces sickness behaviour that peaks 2 to 6 hours later and gradually wanes (a). Depression-like behaviour, as measured by increased immobility in the forced-swim test or the tail-suspension test and decreased preference for a sweet solution, emerges on this background. The development of sickness behaviour requires activation of pro-inflammatory cytokine signalling in the brain in response to peripheral LPS (b). Some of the pro-inflammatory cytokines that induce sickness behaviour also enhance activity of the ubiquitous indoleamine 2,3 dioxygenase (IDO) that peaks at 24 hours post-LPS. Activation of IDO results in decreased tryptophan (TRP) levels and increased production of kynurenine (KYN) and other tryptophan-derived metabolites. Pre-treatment with the second-generation tetracycline minocycline, which has potent anti-inflammatory effects both at the periphery and in the brain, blocks both LPS-induced sickness behaviour and depression-like behaviour. By contrast, administration of 1-methyl tryptophan (1-MT), a competitive inhibitor of IDO, blocks LPS-induced depression-like behaviour without altering LPS-induced sickness behaviour.

Figure 4. Depression as a consequence of decompensation of the mechanisms that regulate sickness

Sickness behaviour in response to an infectious episode is normally reversible owing to the ability of the immune system to clear infectious pathogens and to the recovery mechanisms that oppose the production and action of pro-inflammatory cytokines, both in the periphery and the brain. Clinical evidence shows that depression can develop on a background of sickness with which it shares many of the neurovegetative and psychological components. Studies in animals show the same phenomenon. Decompensation of the mechanisms that regulate sickness behaviour can occur in vulnerable patients whose inflammatory response is more intense because the balance between pro- and anti-inflammatory mediators is shifted towards inflammation (for example, hyperproduction of tumour necrosis factor-α (TNF-α), insufficient production of interleukin (IL)-10 and glucocorticoid resistance). It can also occur in patients whose brain sensitivity to immune-mediated events is higher because of disturbed neurotransmitter metabolism, for example, less efficient serotonergic functioning owing to homozygosity for the short allele of the serotonin transporter gene. HPA, hypothalamus–pituitary–adrenal; SWS, slow-wave sleep; REM, rapid-eye movement sleep.