Abstract
BackgroundActivated microglial cells are an important pathological component in brains of patients with neurodegenerative diseases. The purpose of this study was to investigate the effect of He-Ne (632.8 nm, 64.6 mW/cm2) low-level laser therapy (LLLT), a non-damaging physical therapy, on activated microglia, and the subsequent signaling events of LLLT-induced neuroprotective effects and phagocytic responses.MethodsTo model microglial activation, we treated the microglial BV2 cells with lipopolysaccharide (LPS). For the LLLT-induced neuroprotective study, neuronal cells with activated microglial cells in a Transwell™ cell-culture system were used. For the phagocytosis study, fluorescence-labeled microspheres were added into the treated microglial cells to confirm the role of LLLT.ResultsOur results showed that LLLT (20 J/cm2) could attenuate toll-like receptor (TLR)-mediated proinflammatory responses in microglia, characterized by down-regulation of proinflammatory cytokine expression and nitric oxide (NO) production. LLLT-triggered TLR signaling inhibition was achieved by activating tyrosine kinases Src and Syk, which led to MyD88 tyrosine phosphorylation, thus impairing MyD88-dependent proinflammatory signaling cascade. In addition, we found that Src activation could enhance Rac1 activity and F-actin accumulation that typify microglial phagocytic activity. We also found that Src/PI3K/Akt inhibitors prevented LLLT-stimulated Akt (Ser473 and Thr308) phosphorylation and blocked Rac1 activity and actin-based microglial phagocytosis, indicating the activation of Src/PI3K/Akt/Rac1 signaling pathway.ConclusionsThe present study underlines the importance of Src in suppressing inflammation and enhancing microglial phagocytic function in activated microglia during LLLT stimulation. We have identified a new and important neuroprotective signaling pathway that consists of regulation of microglial phagocytosis and inflammation under LLLT treatment. Our research may provide a feasible therapeutic approach to control the progression of neurodegenerative diseases.
Highlights
Microglia are considered to be central nervous system (CNS)-resident professional macrophages
We examined the phagocytic effects of microglia and the interaction between microglial phagocytosis and neuroinflammation during level laser therapy (LLLT)
While inducing the lowest microglia-mediated neurotoxicity, laser irradiation with a dose of 25 or 50 J/cm2 caused a slight contraction of microglial cells in some cases, probably due to the toxic effect of laser irradiation with high doses
Summary
Microglia are considered to be central nervous system (CNS)-resident professional macrophages. They perform homoeostatic activity and mediate the innate defense system in the normal CNS. Activated microglia can phagocytose fibrillar Aβ (fAβ) or dead cells from the CNS and can secrete different neurotrophic factors for neuronal survival. Once activated, they eventually become more detrimental by releasing proinflammatory molecules (nitric oxide (NO) and TNF-α), causing secondary damage to neurons and the surrounding cellular environment [5]. Activation of microglia has become a hallmark of neurodegeneration It has been debated whether neuroinflammation is an underling cause or a resulting condition in neurodegenerative diseases. The purpose of this study was to investigate the effect of He-Ne (632.8 nm, 64.6 mW/cm2) low-level laser therapy (LLLT), a non-damaging physical therapy, on activated microglia, and the subsequent signaling events of LLLT-induced neuroprotective effects and phagocytic responses
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