Folic Acid Is Able to Polarize the Inflammatory Response in LPS Activated Microglia by Regulating Multiple Signaling Pathways

Abstract

We investigated the ability of folic acid to modulate the inflammatory responses of LPS activated BV-2 microglia cells and the signal transduction pathways involved. To this aim, the BV-2 cell line was exposed to LPS as a proinflammatory response inducer, in presence or absence of various concentrations of folic acid. The production of nitric oxide (NO) was determined by the Griess test. The levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-10 were determined by ELISA. Inducible NO synthase (iNOS), nuclear transcription factor-kappa B (NF-κB) p65, MAPKs protein, and suppressors of cytokine signaling (SOCS)1 and SOCS3 were analyzed by western blotting. TNF-α and IL-1β, as well as iNOS dependent NO production, resulted significantly inhibited by folic acid pretreatment in LPS-activated BV-2 cells. We also observed that folic acid dose-dependently upregulated both SOCS1 and SOCS3 expression in BV-2 cells, leading to an increased expression of the anti-inflammatory cytokine IL-10. Finally, p-IκBα, which indirectly reflects NF-κB complex activation, and JNK phosphorylation resulted dose-dependently downregulated by folic acid pretreatment of LPS-activated cells, whereas p38 MAPK phosphorylation resulted significantly upregulated by folic acid treatment. Overall, these results demonstrated that folic acid was able to modulate the inflammatory response in microglia cells, shifting proinflammatory versus anti-inflammatory responses through regulating multiple signaling pathways.

Folic Acid Improves the Inflammatory Response in LPS-Activated THP-1 Macrophages

“…Cell viability was measured by MTT assay after incubation with folic acid at 11.3 μ M, choline at 105 μ M, vitamin B 12 at 18.5 nM, and the methyl donor mixture. The selected concentrations were within the range proposed by previous studies [ 9 , 17 , 18 ]. Cell viability was not significantly affected by methyl donors at these concentrations (Supplementary Figure 2 ).…”

“…The anti-inflammatory effects exerted by some of these compounds in a variety of inflammatory diseases have been described in previous research. For example, folic acid supplementation improved disease outcomes in subjects with hypertension, diabetes, and stroke by reducing levels of inflammatory markers (CRP, VCAM-1, IL-1 β , and TNF- α ) [ 9 ]. In addition to this, the combined supplementation of folate and vitamin B 12 ameliorated inflammation during pregnancy by modifying the concentration of inflammatory cytokines [ 10 ].…”

The Emerging Role of Curcumin in the Modulation of TLR-4 Signaling Pathway: Focus on Neuroprotective and Anti-Rheumatic Properties

“…However, additional studies have allowed scientists and clinicians to have a better understanding of the benefit derived from the multifunctionality of microglia, since activated microglia is not always harmful being also able to produce anti-inflammatory mediators and neurotrophic factors such as insulin-like growth factor-1, glial cell-derived neurotrophic factor, brain-derived neurotrophic factors, and other factors [132][133][134] leading to beneficial effects.…”

Extracellular Vesicles miRNA Cargo for Microglia Polarization in Traumatic Brain Injury

“…Our previous studies have reported that modulating pro-inflammatory polarization consenting the shifting towards anti-inflammatory polarization improved neuroinflammatory pictures in vivo [ 28 ]. In addition, since in pro-inflammatory polarization the TLR4/NF-κB signaling pathway is significantly activated, pharmacologically targeting this pathway, an attenuation of the inflammatory response was observed [ 29 , 30 , 31 , 32 , 33 ].…”