Fatigue, Sleep, and Autoimmune and Related Disorders

Abstract

Profound and debilitating fatigue is the most common complaint reported among individuals with autoimmune disease, such as systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, celiac disease, chronic fatigue syndrome, and rheumatoid arthritis. Fatigue is multi-faceted and broadly defined, which makes understanding the cause of its manifestations especially difficult in conditions with diverse pathology including autoimmune diseases. In general, fatigue is defined by debilitating periods of exhaustion that interfere with normal activities. The severity and duration of fatigue episodes vary, but fatigue can cause difficulty for even simple tasks like climbing stairs or crossing the room. The exact mechanisms of fatigue are not well-understood, perhaps due to its broad definition. Nevertheless, physiological processes known to play a role in fatigue include oxygen/nutrient supply, metabolism, mood, motivation, and sleepiness-all which are affected by inflammation. Additionally, an important contributing element to fatigue is the central nervous system-a region impacted either directly or indirectly in numerous autoimmune and related disorders. This review describes how inflammation and the central nervous system contribute to fatigue and suggests potential mechanisms involved in fatigue that are likely exhibited in autoimmune and related diseases.

Keywords: autoimmune; cytokines; fatigue; inflammasome; inflammation; neurovascular unit; sleep.

Figure 1

Schematic of proposed NLRP3 inflammasome activation in inducing pro-inflammatory molecules that induce fatigue. Exposure to pathogen-associated molecular pattern or danger-associated molecular pattern that act on their pattern recognition receptors (Signal 1), such as LPS, TNF-α, or IL-1β acting through Toll-like receptor 4, TNFR1, and IL-1R, respectively, will activate the transcriptional factors NF-κB that will prime components of the NLRP3 inflammasome. Additionally, transcription of inflammasome components can also occur through the activation of AP-1. A secondary signal is then required to activate inflammasome formation, including by alterations in metabolism that induce ROS or the activation of the purine type 2X receptors (P2XRs). Upon formation of NLRP3, ASC, and pro-caspase-1, caspase-1 will be allowed to disassociate and cleave the inactive pro-forms of IL-1β and IL-18 into their mature active forms. Upon release, these pro-inflammatory cytokines can alter surrounding cells leading to effects contributing to fatigue.

Figure 2

Increased pro-inflammatory molecules in the brain. Schematic of vagal afferent and efferent modulation of inflammation. The vagal afferents mediate pro-inflammatory signals, such as IL-1β and TNF-α from the periphery including the peritoneum and organs such as the lung intestine, hear, spleen, liver, and lung to stimulate inflammatory cytokines in the nucleus tractus solitarius (NTS). The NTS has projections to multiple brain areas where this pro-inflammatory signal that originates in the periphery leads to enhanced pro-inflammatory cytokine expression in brain areas that affect fatigue and sleep. Conversely, stimulation of the vagal efferents, such as that occurring from cholinergic mechanisms in the brain, such as muscarinic acetylcholine receptors (mAChR) acting through the, NTS, dorsal motor nucleus (DMN), and nucleus ambiguus (NA) can lead to anti-inflammatory reactions in peripheral tissues. The vagal afferents could serve to transfer enhanced inflammatory signals in the periphery occurring from autoimmune and related pathologies into dysregulated inflammatory regulation in the brain to induce fatigue-like behavior. Additionally, abnormal vagal efferent activity could server to affect physiological functions mediating fatigue-like behavior, such as heart rate, bronchoconstriction, and gluconeogenesis.

Figure 3

Diagram of the neurovascular unit in modulating vasohemodynamics. The neurovascular unit at the level of the cerebral microvasculature including the arterioles and capillaries is comprised of endothelial cells, smooth muscle, astrocytes, neurons, pericytes, and is modulated by surrounding microglia and perivascular macrophages. Additionally, alterations in metabolism and inflammation can modulate astrocyte end-feet to modulate cerebral blood flow (CBF). The neurovascular unit modulates blood flow throughout the brain and is regulated by energy needs of the surrounding cells and the vasoconstrictive, such as catecholamines and dopamine, and vasodilative factors, such as IL-1β, TNF-α, and adenosine, that are released by these cells. Pro-inflammatory molecules tend to be vasodilative, reduce vascular resistance, and increase cerebral CBF, while monoamines released by neurons have both vasodilative and vasoconstrictive properties, which can influence blood flow. Vasoconstrictive substances typically increase vascular resistance and reduce CBF.