Neuroimmune Effects Of Irisin In Neurogenesis

Background: Irisin, a novel peptide myokine released from skeletal muscles, has recently been suggested to be the messenger leading to beneficial characteristics of exercise, such as the prevention and slowed progression of neurological diseases as well as mental benefits including higher productivity and increased happiness. Upon exercise Irisin is released into the bloodstream from where it can potentially reach many target organs. Irisin immunoreactivity has been detected in the brain, adipose tissue and cardiovascular system indicating that it exerts a function in these organs (1). A receptor for irisin has not been discovered and its downstream signalling pathways are unknown. Irisin has been shown to express anti-obesity, anti-diabetic properties due its effect on white adipose tissue (2). New evidence suggested a proliferative role for irisin on hippocampal cell lines (3). In our study, we evaluated the potential neurogenic and neuroimmune actions of irisin on neural stem cells (NSC).

Methods: A wide range of irisin concentrations (10, 15, 20, 25, 50, 75, 100 and 150 nM) were tested (t=24h) on NSC from wild type mice (WT, C57BL6) and IL-1β knock-out (KO, C57BL6) mice. The aim of the present in vitro study was to investigate the effects of irisin in NSC proliferation (BrdU), mitochondrial metabolic effect (MTT) and cell death (LDH). Additionally we evaluated the irisin’s effects on immune regulation via interleukin 6 (IL-6), and tumour necrosis factor (TNF) release in NSC and via IL-1β in IL-1β KO NSC. A one-way ANOVA followed by Bonferroni’s multiple comparisons test was performed with statistical significance established at P < 0.05.

Results: i) Irisin was not toxic for the NSC from WT or IL-1β KO mice. ii) Irisin had no effect on metabolic activity and cell proliferation in both NSC groups. iii) Irisin had no effects on TNF levels in both NSC groups. iv) In WT NSC, IL-6 levels increased significantly (p < 0.0001). However in NSC from IL-1β KO, this effect disappeared (p = 0.156).

Conclusion: i) Irisin is not toxic in WT/ IL-1β KO NSC. ii) Irisin has been shown to increase IL-6 levels in WT NSC but not in IL-1β KO NSC, suggesting that irisin’s effect on the increase in IL-6 levels could be mediated via IL-1β.

IL-6 can induce the NSC differentiation into the glial lineage (4). Therefore irisin could exert its effect on the central nervous system by acting via interleukin 6 and the gp130 protein to potentially activate the STAT3 pathway leading to glial differentiation. Glial differentiation would be of good use in the treatments of glia-related diseases such as Multiple sclerosis.

References

(1) Aydin S et al. (2014). Peptides 61: 130-136.

(2) Boström P et al. (2012). Nature 481: 463-468.

(3) Moon HS et al. (2013). Metabolism 62: 1131-1136.

(4) Spooren et al. (2011). Brain Research Reviews 67: 157 - 183