Molecular Neurobiology

, Volume 53, Issue 2, pp 1195–1219 | Cite as

The Neuro-Immune Pathophysiology of Central and Peripheral Fatigue in Systemic Immune-Inflammatory and Neuro-Immune Diseases

  • Gerwyn Morris
  • Michael Berk
  • Piotr Galecki
  • Ken Walder
  • Michael Maes


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.


Chronic fatigue syndrome CFS Inflammation Oxidative and nitrosative stress Tryptophan catabolites Neuroprogression 


Funding and competing interests

No specific funding was obtained for this specific review.

GM, MB, PG, and MM declare that they have no competing interests.

Authors’ contributions

GM and MM participated in the design of this review, while PG and MB helped to draft the paper. All authors read and approved the final version.


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Gerwyn Morris
    • 1
  • Michael Berk
    • 2
    • 3
    • 4
    • 5
  • Piotr Galecki
    • 6
  • Ken Walder
    • 7
  • Michael Maes
    • 2
    • 8
    • 9
    • 10
  1. 1.Tir Na NogLlanelliUK
  2. 2.IMPACT Strategic Research Centre, School of MedicineDeakin UniversityGeelongAustralia
  3. 3.Orygen Youth Health Research Centre and the Centre of Youth Mental HealthParkvilleAustralia
  4. 4.The Florey Institute for Neuroscience and Mental HealthUniversity of MelbourneParkvilleAustralia
  5. 5.Department of PsychiatryUniversity of MelbourneParkvilleAustralia
  6. 6.Department of Adult PsychiatryMedical University of LodzLodzPoland
  7. 7.Metabolic Research UnitDeakin UniversityGeelongAustralia
  8. 8.Department of Psychiatry, Faculty of MedicineChulalongkorn UniversityBangkokThailand
  9. 9.Health Sciences Graduate Program, Health Sciences CenterState University of LondrinaLondrinaBrazil
  10. 10.Impact Strategic Research CenterDeakin UniversityGeelongAustralia

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