title: The Neuro-Immune Pathophysiology of Central and Peripheral Fatigue in Systemic Immune-Inflammatory and Neuro-Immune Diseases.
abstract: Many patients with systemic immune-inflammatory and neuro-inflammatory disorders, including depression, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's disease, cancer, cardiovascular disorder, Parkinson's disease, multiple sclerosis, stroke, and chronic fatigue syndrome/myalgic encephalomyelitis, endure pathological levels of fatigue. The aim of this narrative review is to delineate the wide array of pathways that may underpin the incapacitating fatigue occurring in systemic and neuro-inflammatory disorders. A wide array of immune, inflammatory, oxidative and nitrosative stress (O&NS), bioenergetic, and neurophysiological abnormalities are involved in the etiopathology of these disease states and may underpin the incapacitating fatigue that accompanies these disorders. This range of abnormalities comprises: increased levels of pro-inflammatory cytokines, e.g., interleukin-1 (IL-1), IL-6, tumor necrosis factor (TNF) α and interferon (IFN) α; O&NS-induced muscle fatigue; activation of the Toll-Like Receptor Cycle through pathogen-associated (PAMPs) and damage-associated (DAMPs) molecular patterns, including heat shock proteins; altered glutaminergic and dopaminergic neurotransmission; mitochondrial dysfunctions; and O&NS-induced defects in the sodium-potassium pump. Fatigue is also associated with altered activities in specific brain regions and muscle pathology, such as reductions in maximum voluntary muscle force, downregulation of the mitochondrial biogenesis master gene peroxisome proliferator-activated receptor gamma coactivator 1-alpha, a shift to glycolysis and buildup of toxic metabolites within myocytes. As such, both mental and physical fatigue, which frequently accompany immune-inflammatory and neuro-inflammatory disorders, are the consequence of interactions between multiple systemic and central pathways.
authors.affiliation: Tir Na Nog, Bryn Road seaside 87, Llanelli, SA152LW, Wales, UK.
authors.forename: Gerwyn
authors.initials: G
authors.lastname: Morris
authors.affiliation: IMPACT Strategic Research Centre, School of Medicine, Deakin University, P.O. Box 291, Geelong, 3220, Australia.|Orygen Youth Health Research Centre and the Centre of Youth Mental Health, Poplar Road 35, Parkville, 3052, Australia.|The Florey Institute for Neuroscience and Mental Health, University of Melbourne, Kenneth Myer Building, Royal Parade 30, Parkville, 3052, Australia.|Department of Psychiatry, University of Melbourne, Level 1 North, Main Block, Royal Melbourne Hospital, Parkville, 3052, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Berk
authors.affiliation: Department of Adult Psychiatry, Medical University of Lodz, Lodz, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Galecki
authors.affiliation: Metabolic Research Unit, Deakin University, Geelong, Australia.
authors.forename: Ken
authors.initials: K
authors.lastname: Walder
authors.affiliation: IMPACT Strategic Research Centre, School of Medicine, Deakin University, P.O. Box 291, Geelong, 3220, Australia. dr.michaelmaes@hotmail.com.|Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. dr.michaelmaes@hotmail.com.|Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina, Brazil. dr.michaelmaes@hotmail.com.|Impact Strategic Research Center, Deakin University, Geelong, Australia. dr.michaelmaes@hotmail.com.
authors.forename: Michael
authors.initials: M
authors.lastname: Maes
mesh_terms: D001921:Brain / Q000473:pathology / Q000503:physiopathology; D015673:Fatigue Syndrome, Chronic / Q000276:immunology* / Q000503:physiopathology*; D006801:Humans; D007154:Immune System Diseases / Q000503:physiopathology*; D007249:Inflammation / Q000473:pathology*; D009132:Muscles / Q000473:pathology / Q000503:physiopathology; D018377:Neurotransmitter Agents / Q000378:metabolism
chemical_list: D018377:Neurotransmitter Agents
keywords: CFS; Chronic fatigue syndrome; Inflammation; Neuroprogression; Oxidative and nitrosative stress; Tryptophan catabolites