The neuroimmune basis of fatigue

Abstract

The exact nature and pathophysiology of fatigue remain largely elusive despite its high prevalence in physically ill patients. Studies on the relationship between the immune system and the central nervous system provide a new perspective on the mechanisms of fatigue. Inflammatory mediators that are released by activated innate immune cells at the periphery and in the central nervous system alter the metabolism and activity of neurotransmitters, generate neurotoxic compounds, decrease neurotrophic factors, and profoundly disturb the neuronal environment. The resulting alterations in fronto-striatal networks together with the activation of insula by inflammatory interoceptive stimuli underlie the many dimensions of fatigue including reduced incentive motivation, decreased behavioral flexibility, uncertainty about usefulness of actions, and awareness of fatigue.

Fig. 1. Peripheral and central mechanisms of inflammation-associated central fatigue

Systemic inflammation, which can be caused by a number of factors, involves both innate immune cells and T lymphocytes. The proinflammatory cytokines that are produced de novo by these cells affect the bioavailability of amino acid precursors of neurotransmitters. Specifically, peripheral proinflammatory cytokines activate guanosine-triphosphate cyclohydrolase-1 (GTP-CH1), which mediates synthesis of neopterin by macrophages. This results in a relative deficit in tetrahydrobiopterin (BH4), an essential cofactor of aromatic amino acid hydroxylase enzymes used in the synthesis of dopamine, norepinephrine and serotonin. BH4 is also a co-factor for the synthesis of nitric oxide by inducible nitric oxide synthase. Proinflammatory cytokines also activate indoleamine 2,3 dioxygenase (IDO) in macrophages and dendritic cells, which degrades tryptophan (TRP) along the kynurenine (KYN) pathway. Kynurenine competes with tryptophan for entry into the brain. Kynurenine is further metabolized by activated microglia into 3-hydroxy kynurenine and quinolinic acid, which are both potent radical donors. Quinolinic acid acts also as an agonist of N-methyl-D-aspartic acid (NMDA) receptors and promotes neurotoxicity. The conversion of kynurenine into kynurenic acid, which acts as an antagonist of NMDA receptors, takes place in astrocytes. However, in conditions of inflammation this potentially neuroprotective pathway is less effective than the pathway leading to quinolinic acid. Peripheral inflammatory mediators activate immune-to-brain communication pathways including afferent nerves. This leads to the local synthesis of inflammatory mediators that affect neuronal function and structure directly or via impairment of the neuronal environment, reduction of the synthesis of neurotrophic factors, and oxidative stress. These effects are rarely sufficient to cause neurotoxicity but they can easily potentiate the neurotoxic activity of a number of other factors. Activation of the pituitary-adrenal axis by proinflammatory cytokines under the combined effect of corticotrophin-releasing hormone and vasopressin (not shown in the graph) should normally contribute to down-regulation of the inflammatory response both at the periphery and in the central nervous system via the production of cortisol and the anti-inflammatory properties of vasopressin. However, this effect can be compromised by the development of cortisol resistance during inflammation. Adverse behavioral responses are the ultimate consequence of activation of these pathways. Red arrows signify the direction of change in a specific inflammatory mediator, enzyme or molecule following systemic inflammation, processes at similar levels, (e.g. both peripheral and central causes of inflammation) highlighted with a common color.

Fig. 2

A model for deconstructing fatigue in neurobehavioral units associated with dysfunction of the fronto-striatal network in response to microglia activation and activation of the anterior insula by interoceptive visceral afferents. Note that the connection from the insula to the ventral striatum involves the anterior cingulate cortex (not shown).