Fatigue in inflammatory rheumatic disorders: pathophysiological mechanisms

Abstract

Today, inflammatory rheumatic disorders are effectively treated, but many patients still suffer from residual fatigue. This work presents pathophysiological mechanisms of fatigue. First, cytokines can interfere with neurotransmitter release at the preterminal ending. Second, a long-term increase in serum concentrations of proinflammatory cytokines increase the uptake and breakdown of monoamines (serotonin, noradrenaline and dopamine). Third, chronic inflammation can also decrease monoaminergic neurotransmission via oxidative stress (oxidation of tetrahydrobiopterin [BH4]). Fourth, proinflammatory cytokines increase the level of enzyme indoleamine-2, 3-dioxygenase activity and shunt tryptophan away from the serotonin pathway. Fifth, oxidative stress stimulates astrocytes to inhibit excitatory amino acid transporters. Sixth, astrocytes produce kynurenic acid that acts as an antagonist on the α7-nicotinic acetylcholine receptor to inhibit dopamine release. Jointly, these actions result in increased glutamatergic and decreased monoaminergic neurotransmission. The above-described pathophysiological mechanisms negatively affect brain functioning in areas that are involved in fatigue.

Keywords: fatigue; inflammation; mechanisms; pathophysiology; rheumatic disorders.

Fig. 1

The localization of the brain areas with different neurotransmitters involved in fatigue and the relevant pathways Red: glutamate neurons in dlPFC, vmPFC. Grey: acetylcholine neurons in the MS, NB, PTN. Green-blue: dopamine neurons in VTA, SNpc. Yellow: serotonin neurons in DR, MR. Purple: melatonin pinealocyte in the pineal gland. Blue: noradrenaline neurons, LC. (a) Corticostriatal glutamatergic projection. (b, c) Cholinergic projections to prefrontal cortex/hippocampus. (d) Cholinergic projection to dorsal striatum. (e, f) Serotonergic projections to prefrontal cortex, OFC, ACC. (g) Dopaminergic projection from VTA to nucleus accumbens (mesolimbic pathway). (h) Dopaminergic projection from SNpc to dorsal striatum (nigrostriatal pathway). (i, j) (green-blue) Dopaminergic projection from VTA to cortex (mesocortical pathway). (i, j) (blue) Noradrenergic projection from LC to dlPFC and ACC. dlPFC: dorsolateral prefrontal cortex; vmPFC: ventromedial prefrontal cortex; MS: medial septal nucleus; NB: nucleus basalis of Meynert; PTN: pontomesencephalotegmental nuclei; VTA: ventral tegmental area; SNpc: substantia nigra pars compacta; DR: dorsal raphe nucleus; MR: median raphe nucleus; LC: locus coeruleus; OFC: orbitofrontal cortex; ACC: anterior cingulate cortex.

Fig. 2

The different types of fatigue in chronic inflammation Brain monoamines (orange: serotonin neurons in raphe nuclei; green-blue: dopamine neurons in ventral tegmental area or substantia nigra pars compacta; and blue: noradrenaline neurons in locus coeruleus play an important modulatory role in (i) motivational fatigue; (ii) physical fatigue; (iii) cognitive fatigue. The anatomical relations are given in figure 1.

Fig. 3

Pathophysiological mechanisms how inflammation changes brain chemistry (1) Inhibition of noradrenaline release by cytokines. (2) Increased uptake of monamines into the nerve ending reduces neurotransmitters in the synaptic cleft. Monamine transporters are activated by cytokines. (3) Changes in phenylalanine hydroxylase and tyrosine hydroxylase (TH) reduce catecholamine synthesis. (4) Changes in tryptophan metabolism lead to reduced serotonin through inhibition of TPH, through activation of IDO, and through activation of KMO. (5) Reactive oxygen and nitrogen species inhibit glutamate transporters, especially EAAT2 on astrocytes. Consequently, glutamate increases in the synaptic cleft. (6) Reactive oxygen/nitrogen species also increase kynurenic acid from astrocytes. Finally, cytokines stimulate activity of GTP-CH1 to increase neopterin but to decrease BH4. Because BH4 is important for generation of monamines, the lack of BH4 supports fatigue and depression. SERT: serotonin transporter; DAT: dopamine transporter; NET: noradrenaline transporter; TPH: tryptophan hydroxylase; IDO: indoleamine-2, 3-dioxygenase; KMO: kynurenine-3-monooxygenase; EAAT2: excitatory amino acid transporter 2; GTP-CH1: guanosine triphosphate cyclohydrolase I; BH4: tetrahydrobiopterin.

Fig. 4

Inflammation-induced changes in neurotransmission in different areas and different cell types mGlu2 receptor, metabotropic glutamate receptor 2 (autoreceptor for glutamate, that upon activation, inhibits the emptying of vesicular contents at the presynaptic terminal of glutamatergic neurons). SERT: serotonin transporter; DAT: dopamine transporter; NET: noradrenaline transporter.