The biological basis of chronic fatigue: neuroinflammation and innate immunity

Chronic fatigue is common in cancer, neurodegenerative, and chronic inflammatory diseases and is regarded by many patients as their absolutely worst problem. Lately, fatigue is increasingly understood to have a genetic and molecular basis.Biologically, fatigue occurs as part of the sickness behavior response, a complex and automated behavior triggered by the activation of innate immunity and neuroinflammation. IL-1β causes neuronal activation in the brain and subsequent fatigue. In addition to proinflammatory molecules, potential partners in the complex brain signaling of fatigue include downregulatory mechanisms for inflammation and cellular stress responses and the neuropeptide hypocretin-1. These mechanisms all become constantly activated in chronic conditions. Genetic studies indicate that fatigue may have evolved to enhance survival during infection and injury.Fatigue is a major clinical problem. Finding the right treatment is challenging, as no specific options exist and only a few of the mechanisms contributing to fatigue are known. Because fatigue is generated in the brain, further studies should focus on proteomics and specific candidate proteins in cerebrospinal fluid. Studies on genetic variants, gene activation, and epigenetics are also required.