FNDC5/Irisin System in Neuroinflammation and Neurodegenerative Diseases: Update and Novel Perspective

Abstract

Irisin, the circulating peptide originating from fibronectin type III domain-containing protein 5 (FNDC5), is mainly expressed by muscle fibers under peroxisome proliferator-activated receptor gamma coactivator 1-alpha PGC1α control during exercise. In addition to several beneficial effects on health, physical activity positively affects nervous system functioning, particularly the hippocampus, resulting in amelioration of cognition impairments. Recently, FNDC5/irisin detection in hippocampal neurons and the presence of irisin in the cerebrospinal fluid opened a new intriguing chapter in irisin history. Interestingly, in the hippocampus of mice, exercise increases FNDC5 levels and upregulates brain-derived neurotrophic factor (BDNF) expression. BDNF, displaying neuroprotection and anti-inflammatory effects, is mainly produced by microglia and astrocytes. In this review, we discuss how these glial cells can morphologically and functionally switch during neuroinflammation by modulating the expression of a plethora of neuroprotective or neurotoxic factors. We also focus on studies investigating the irisin role in neurodegenerative diseases (ND). The emerging involvement of irisin as a mediator of the multiple positive effects of exercise on the brain needs further studies to better deepen this issue and the potential use in therapeutic approaches for neuroinflammation and ND.

Biological Aspects of Selected Myokines in Skeletal Muscle: Focus on Aging

“…Irisin is widely distributed in the human body and is involved in metabolic processes such as the transformation from white to brown adipocytes and the mechanism of insulin resistance [122]. However, irisin also appears to have a positive effect on cognitive function and to play a role in bone metabolism regulation [2,123]. Finally, recent studies have shown that malignant cells have a higher concentration of irisin than normal ones [124].…”

FNDC5/Irisin: Physiology and Pathophysiology

“…Taken together, all these data suggest that although no specific receptor of irisin has been identified yet, it exerts its action via αV/β5 integrins in bone and fat tissues. Conversely, these specific effects of irisin via interaction with αV/β5 are not completely understood in vivo, either due to the ability of αV/β5 to interact with other ligands, or the binding affinity of irisin with other integrin complexes [ 36 ]. Although αV/β5 integrins have been shown as irisin receptors in some tissues, there is also a possibility of other receptors both within and outside of the integrin family.…”

“…Irisin is found in cerebral Purkinje cells, hypothalamus, and cerebrospinal fluid, and plays some essential roles in the central nervous system [ 10 , 49 ]. Various evidence showed that irisin crosses the blood–brain barrier, from where it induces BDNF, which is involved in regulating synaptic plasticity [ 36 , 50 ]. Earlier, it was reported that irisin enhances cell proliferation in H19-7 HN cells of mice [ 51 ].…”

Physical Exercise, a Potential Non-Pharmacological Intervention for Attenuating Neuroinflammation and Cognitive Decline in Alzheimer’s Disease Patients

“…Irisin crosses the BBB, attenuates brain neuroinflammation and improves hippocampal memory and learning function by increasing expression of BDNF in microglia and astrocytes. BDNF has anti-inflammatory effects by attenuating NFκB, GSK3β, p38 and JNK activity in microglia and astrocytes, thus reducing the release of pro-inflammatory cytokines of IL6 and IL1β in the brain [ 175 ]. Irisin also decreases the expression of pro-inflammatory cyclooxygenase-2 and AKT phosphorylation [ 175 ].…”