Irisin protects against neuronal injury induced by oxygen-glucose deprivation in part depends on the inhibition of ROS-NLRP3 inflammatory signaling pathway

Abstract

Recent studies found that irisin, a newly discovered skeletal muscle-derived myokine during exercise, is also synthesized in various tissues of different species and protects against neuronal injury in cerebral ischemia. The NOD-like receptor pyrin 3 (NLRP3) inflammasome play an important role in detecting cellular damage and mediating inflammatory responses to aseptic tissue injury during ischemic stroke. However, it is unclear whether irisin is involved in the regulation of NLRP3 inflammasome activation during ischemic stroke. In the present study, PC12 neuronal cells were exposed to oxygen-glucose deprivation (OGD), exogenous irisin (12.5, 25, 50nmol/L) or NLRP3 inhibitor glyburide (50, 100, 200μmol/L) were used as an intervention reagent, NLRP3 was over-expressed or suppressed by transfection with a NLRP3 expressing vector or NLRP3-specifc siRNA, respectively. Our data showed that both irisin and its precursor protein fibronectin type III domain containing 5 (FNDC5) expression were significantly down-regulated (p<0.05); but oxidative stress and ROS-NLRP3 inflammasome signaling were activated by OGD (p<0.05); treatment with irisin or inhibition of NLRP3 reversed OGD-induced oxidative stress and inflammation (p<0.05). However, these irisin-mediated effects were blunted by over-expression NLRP3 (p<0.05). Taken together, our results firstly revealed that irisin mitigated OGD-induced neuronal injury in part via inhibiting ROS-NLRP3 inflammatory signaling pathway, suggesting a likely mechanism for irisin-induced therapeutic effect in ischemic stroke.

Constitutive PGC-1α Overexpression in Skeletal Muscle Does Not Improve Morphological Outcome in Mouse Models of Brain Irradiation or Cortical Stroke

“…Even though FNDC5 is involved in neuronal differentiation, irisin did not induce neuronal differentiation in a murine neural stem cell line, but increased proliferation at 10 times the physiological concentration (126). Irisin protected against neuronal cell injury due to oxygen and glucose depravation (127), as well as improved morphological and functional outcome in a mouse model of middle cerebral artery occlusion (128). Further, blockade of irisin with an intravenously administered antibody attenuated the neuroprotective effects of physical exercise against cerebral ischemia.…”

The Role of Irisin in Alzheimer’s Disease

“…Irisin protects neurons by attenuating the secretion of pro-inflammatory cytokine such as tumor necrosis factor (TNF)-α through Akt/ERK1/2 signaling [ 114 ]. In addition, irisin protects neurons by suppressing ROS-NLRP3 inflammatory signaling in ischemic conditions [ 115 ]. This study demonstrated that PC12 cells as neuronal cells inhibited the expression of pro-inflammatory cytokine, interleukin (IL)-1β and the activation of caspase 1 signaling as apoptosis signaling under ischemic condition (i.e., oxygen and glucose deprivation conditions) [ 115 ].…”

“…In addition, irisin protects neurons by suppressing ROS-NLRP3 inflammatory signaling in ischemic conditions [ 115 ]. This study demonstrated that PC12 cells as neuronal cells inhibited the expression of pro-inflammatory cytokine, interleukin (IL)-1β and the activation of caspase 1 signaling as apoptosis signaling under ischemic condition (i.e., oxygen and glucose deprivation conditions) [ 115 ]. Given that the enhancement of neurogenesis could potentially improve the impaired synaptic plasticity and memory dysfunction found in AD [ 26 , 28 , 29 ], irisin may be a potential therapeutic target for AD as it promotes both neurogenesis and neuronal cell survival.…”

Evidence and perspective for the role of the NLRP3 inflammasome signaling pathway in ischemic stroke and its therapeutic potential (Review)

“…Probenecid, a pannexin 1 inhibitor, has also been found to induce astrocyte death and ROS generation, attenuate expression levels of NLRP3 and inhibit the extracellular release of IL-1β (101). Mcc950 and glyburide, both NLRP3 oligomerization inhibitors, reduce infarction volume, neuronal apoptosis, and neurological impairment, and have anti-oxidative stress and anti-inflammatory effects, respectively (102)(103)(104)(105). Recently, several natural compounds, including resveratrol, paeoniflorin and sinomenine, were also demonstrated to reduce cerebral infarction volume, decrease brain water content, improve neurological scores and grip strength, and prevent neuronal cell death following ischemic stroke, through downregulating the expression of the components of the NLRP3 inflammasome and their downstream proteins and attenuating its activation (106)(107)(108).…”