Fatigue in chronic inflammation

Role of inflammation in fatigue

The mechanisms of fatigue are complex and have been studied in animal models and humans.
Because fatigue could be explained by loss of muscle mass or altered mood, Norden
et al. 55] proposed a model to discriminate between these phenomena: some colon tumor-bearing
mice demonstrated signs of fatigue (decreased voluntary wheel-running activity) and
depressed mood (resignation and anhedonia), with no association with decreased normalized
contractile properties of skeletal muscle of the limb. So fatigue seemed linked more
to behavior than muscle activity.

Inflammation could play an important role (Table 1). The injection of IL-1 in murine models decreased social exploration and increased
hypersomnia and body weight loss, which were all improved by the administration of
anti-inflammatory IL-1RA or IL-10 56], 57]. Moreover, in the model of tumor-induced fatigue in mice seen earlier, fatigue was
associated with increased levels of IL-1 and IL-6 in the brain, and treatment with
minocycline, an anti-inflammatory agent, improved grip strength without reducing tumor
growth or muscle mass 55].

Table 1. Possible mechanisms involved in fatigue

The role of inflammation in fatigue has also been shown in patients. Indeed, in those
with chronic fatigue syndrome (CFS), fatigue intensity was associated with high circulating
IL-8 levels 58]. Moreover, in an observational study of military personnel with insomnia, CRP level
was reduced more in the restorative sleep group than in those with persistent insomnia
59]. In RA patients, a meta-analysis of therapeutic studies showed that inhibiting levels
of some pro-inflammatory cytokines by biologic agents such as anti-TNF, anti-IL-6,
CTLA4 immunoglobulin or anti-CD20 significantly decreased the level of fatigue whatever
the therapy 46].

Otherwise, fatigue could be due to inflammation-induced anemia by decreasing iron
levels mediated by IL-6-induced hepcidin and thyroid insufficiency or decreased hypothalamic-pituitary-adrenal
(HPA) axis activity and resistance to glucocorticoids (Fig. 2 and Table 1) 27], 60], 61]. In this system, the release of adrenocorticotropic hormone is affected by the sleep
cycle, but in some diseases, the circadian cortisol cycle is abnormally flattened
61]. Therefore, neurological phenomena could be involved in fatigue (Table 1). The role of CNS neurotransmitters was mentioned in recent reviews 27], 62], 63]: fatigue was found to be related to polymorphism in catechol-O-methyltransferase
(COMT) and low levels of tryptophan, an amino acid involved in the synthesis of serotonin
or impaired brain dopamine and norepinephrine transmission 27], 62], 63]. In parallel, the autonomic activity was altered in a model of fatigue induced by
a cognitive task, the Kana Pick-out Test (alternating open and closed eyes): VAS fatigue
score was associated with decreased parasympathetic and increased sympathetic sinus
modulation as evaluated by electrocardiography 64]. Moreover, this model of induced fatigue activated the dorsolateral prefrontal cortex
and cingulate cortex as assessed by functional magnetic resonance imaging (MRI) 64], 65].

Fig. 2. Mechanisms of interaction between peripheral inflammation, the nervous system and
the hypothalamic-pituitary-adrenal (HPA) axis involved in the fatigue process. In
the HPA axis, the hypothalamus contains neurons that synthesize corticotropin-releasing
hormone (CRH), which regulates adrenocorticotropic hormone (ACTH) by the pituitary
gland. ACTH stimulates the synthesis of glucocorticoids such as cortisol by the adrenal
cortex and catecholamines by the adrenal medulla of the adrenal gland. Cortisol could
have a negative feedback mechanism on the brain. Glucocorticoids inhibit many functions
of leukocytes and the production of pro-inflammatory cytokines (interleukin (IL)-6
and IL-1) by immune cells. ACTH and CRH have pro-inflammatory properties and IL-1,
IL-6 and tumor necrosis factor (TNF)-? activate the HPA axis. The peripheral nervous
system can affect inflammation: the sympathetic neurons of the autonomic nervous system
(ANS) secrete pro- and anti-inflammatory neuropeptides. These pro-inflammatory cytokines
could enter central nervous system (CNS) areas by the permeable blood–brain barrier
or facilitate the release of second messengers to induce cytokine activity in the
brain. With excess inflammation, the activity of some CNS neurotransmitters could
be altered

Systemic inflammation could affect these central mechanisms. Under some circumstances,
such as chronic anxiety, posttraumatic stress, and local or general inflammation diseases,
the HPA axis was deregulated and the persistent secretion of corticoids induced glucocorticoid
resistance 66]. The HPA axis has also been shown to interact with the immune system (Fig. 2) 61]. Moreover, although the brain is considered an immunologically privileged site, systemic
infection or inflammation can have a profound effect on the CNS. In an animal model
of inflammation, the peripheral administration of lipopolysaccharide increased IFN-stimulated
genes in the brain 66], 67]. Peripheral pro-inflammatory cytokines could have a direct action when they enter
CNS areas where the blood–brain barrier is permeable and an indirect action when they
facilitate the release of second messengers to induce cytokine activity in the brain
or when they activate the vagus or other afferent nerves 14]. TNF-? could participate in microglial activation in promoting rolling and adhesion
of leukocytes along cerebral endothelial cells, which negatively affects dopaminergic
neurotransmission 27], 63], 66]–68]. However, anti-TNF agents are unable to penetrate the blood–brain barrier 69]. Inflammatory cytokines would also be responsible for a relative deficit in tetrahydrobiopterin
used in the synthesis of the neurotransmitters dopamine, norepinephrine and serotonin
63]. The CNS releases norepinephrine, which is responsible for upregulating IL-1, IL-6
and TNF 66]. However, most studies examined acute inflammation, and the role of neurotransmitters
in chronic inflammation is not well established. A bidirectional interaction between
the neuroendocrine system and peripheral inflammation could play a role in fatigue.

Role of inflammation in pain

Pain has been investigated in animal models and humans. In animal models, pain could
result from complex interactions between joint inflammation and altered pain processing:
a peripheral mechanism (for example, increased innervation of the synovium; increased
dorsal root ganglia expression of substrance P, calcitonin gene-related peptide and
neuropeptide Y; increased expression of tyrosine kinase receptor A for nerve growth
factor and neuronal death) and central mechanism (for example, nociceptive pathway
activity, increased sensitivity of spinal neurons via glian, and activation via interleukin
(IL-1, IL-6 and TNF), opiod expression in ganglia, central sensitization). Dopamine
and serotonin systems are also involved in pain: COMT gene expression and polymorphisms of serotonin transporter genes were found associated
with pain 62]. Patients with RA showed production of peripheral pain agents, pro-inflammatory cytokines
(IL-1, IL-6 and TNF with different actions on responsiveness of A?-fibers, C-fibers
and the effect of neutralization on mechanical hyperalgesia) and nerve growth factor
in synovium or synovial fluid, which sensitized peripheral receptors 70]. TNF-? injected in mouse joints induced persistent sensitization of nociception with
noxious stimuli, with a dose-dependent effect, with prevention by injection of an
anti-TNF agent 71]. Endogenous opioids, somatostatin, lipid mediators and anti-inflammatory cytokines
(IL-4 and IL-10) were also present in synovial tissue, but their roles remain to be
determined. Central pain processing was increased in RA patients, with a change in
neuronal adaptive response and increased activity of the thalamus, secondary sensory
cortex and limbic system, which could be modulated by emotional processing or low
mood 70], 72]. Proinflammatory cytokines could have a direct action on pain via sensory neurons
or an indirect action via inflammatory mediators such as prostaglandins 70].

Role of inflammation in altered central nervous system activity

Because fatigue is also often associated with anxiety and depression in inflammatory
rheumatism, it may be due in part to a neurological phenomenon. Pro-inflammatory cytokines
could be involved: administration of IL-1?, IL-6 or TNF-? in mice increase behavioral
symptoms such as social exploration 56], 68]. A review showed that blood levels of some inflammatory cytokines, such as mitogen-stimulated
cytokines and adipokines, were higher with depression 68]. A meta-analysis of 24 publications reporting on levels of cytokines in depressed
patients found increased levels of TNF-? and IL-6 but not IL-1?, IL-4, IL-2, IL-8,
IL-10 or IFN-? 73]. In some of these studies, however, this association could represent a subset of
patients; for example, those with a high degree of depression, who were older and
had comorbidities 74]. In older patients of the Rotterdam study, despite no association between blood levels
of IL-6 and CRP and depressive symptoms, high levels of these inflammatory proteins
predicted depressive symptoms 5 years later 74]. Moreover, in pooling the data for five placebo-controlled trials, Iyengar et al.
75] showed that treatment with nonsteroidal anti-inflammatory drugs (the ibuprofen or
naproxen group and the celecoxib group) was associated with decreased depression score
and showed a trend to changed classification of depression at 6 weeks. Moreover, antidepressive
agents might inhibit the production of pro-inflammatory IL-6 and stimulate anti-inflammatory
IL-4, IL-10 and IL-1RA 76]. However, levels of the proinflammatory cytokines could also be altered by stressors
or lifestyle factors associated with depression. Indeed, stress caused by major life
events such as interpersonal loss or social rejection was associated with levels of
pro-inflammatory IL-6 and TNF-? and also CRP, especially in depressed patients 73].

Stress was also associated with high levels of the pro-inflammatory intracellular
transcription factors NF?B and inhibitor of kB and modulated genome-wide expression
levels 66]. Thus, inflammation and depression seem to be linked, but which one affects the other
is difficult to distinguish and probably there is an interaction between both.