Central pathways causing fatigue in neuro-inflammatory and autoimmune illnesses

Abstract

Background: The genesis of severe fatigue and disability in people following acute pathogen invasion involves the activation of Toll-like receptors followed by the upregulation of proinflammatory cytokines and the activation of microglia and astrocytes. Many patients suffering from neuroinflammatory and autoimmune diseases, such as multiple sclerosis, Parkinson's disease and systemic lupus erythematosus, also commonly suffer from severe disabling fatigue. Such patients also present with chronic peripheral immune activation and systemic inflammation in the guise of elevated proinflammtory cytokines, oxidative stress and activated Toll-like receptors. This is also true of many patients presenting with severe, apparently idiopathic, fatigue accompanied by profound levels of physical and cognitive disability often afforded the non-specific diagnosis of chronic fatigue syndrome.

Discussion: Multiple lines of evidence demonstrate a positive association between the degree of peripheral immune activation, inflammation and oxidative stress, gray matter atrophy, glucose hypometabolism and cerebral hypoperfusion in illness, such as multiple sclerosis, Parkinson's disease and chronic fatigue syndrome. Most, if not all, of these abnormalities can be explained by a reduction in the numbers and function of astrocytes secondary to peripheral immune activation and inflammation. This is also true of the widespread mitochondrial dysfunction seen in otherwise normal tissue in neuroinflammatory, neurodegenerative and autoimmune diseases and in many patients with disabling, apparently idiopathic, fatigue. Given the strong association between peripheral immune activation and neuroinflammation with the genesis of fatigue the latter group of patients should be examined using FLAIR magnetic resonance imaging (MRI) and tested for the presence of peripheral immune activation.

Summary: It is concluded that peripheral inflammation and immune activation, together with the subsequent activation of glial cells and mitochondrial damage, likely account for the severe levels of intractable fatigue and disability seen in many patients with neuroimmune and autoimmune diseases.This would also appear to be the case for many patients afforded a diagnosis of Chronic Fatigue Syndrome.

Figure 1

Pathways associated with secondary fatigue. Prolonged and or excessive stimulation of membrane bound Toll-like receptors (TLRs) results in the production of pro-inflammatory cytokines (PICs) and reactive oxygen and nitrogen species (ROS/RNS) at sufficiently high concentrations to cause macromolecule damage leading to the production of redox-derived damage-associated molecular patterns (DAMPs). The presence of such DAMPs leads to chronic engagement of TLRs and a spiraling, self-amplifying pattern of increasing ROS/RNS and PICs in a TLR radical cycle. Increasing levels of ROS/RNS damage mitochondrial lipids and proteins leading to dissipation of the mitochondrial membrane potential and inhibition of the electron transport chain. This leads to compromised oxidative phosphorylation and the production of ROS making another major contribution to the inflammatory milieu and another element in the development of a vicious spiral of bioenergetics decline. Elevated levels of PICs in the periphery activate microglia and astrocytes in the brain leading to the production of elevated PICs and ROS/RNS causing mitochondrial and metabolic dysfunction. This figure is original.

Figure 2

This figure describes the putative role of immune brain communication in the pathogenesis of severe intractable fatigue. Toll-like receptors (TLRs) on antigen presentation cells (APCs) may be activated by pathogen- or damage-associated molecular patterns (PAMPs/DAMPs) leading to the activation of nuclear factor-κB (NF-κB) and the subsequent upregulation of pro-inflammatory cytokines (PICs), including interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α, and reactive oxygen and nitrogen species (ROS/RNS). These radical species may further damage macromolecules, increasing levels of redox-derived DAMPs which further engage TLRs in a self-sustaining cycle. PIC signals reach the brain via the afferent arm of the vagus nerve, engagement with transporters in the blood brain barrier (BBB) and passive diffusion. Inflammatory signaling from the periphery activates microglia which produce a range of neurotoxic molecules activating astrocytes causing a loss of brain homoeostasis and disruption of the BBB. The latter allows abnormally high numbers of activated T and B cells and macrophages to circulate between the periphery and the brain. This figure is original.

Figure 3

This figure depicts shared pathways in the illnesses described in this paper that may cause secondary fatigue. Activation of Toll-like receptors 2/4 (TLR2/4) by pathogen- and damage-associated molecular patterns (PAMPs/DAMPs) leads to the production of interleukin (IL)-1β, tumor necrosis factor (TNF)-α and IL-6 together with elevated levels of reactive oxygen and nitrogen species (ROS/RNS). IL-1β is a primary source of secondary fatigue and together with the other cytokines acts as a secondary source of fatigue via the inhibition of mitochondrial performance and the provocation of metabolic dysfunction in the brain via the activation of astrocytes and microglia. ROS/RNS can also be a primary cause of secondary fatigue by damaging lipids and proteins which are essential for the performance of mitochondria and inhibiting the electron transport chain. These actions lead to impaired mitochondrial performance which is also a source of fatigue in a similar manner as found in syndromic mitochondrial diseases. This figure is original.