Fatty Acid Amide Hydrolase (FAAH) Inhibition Modulates Amyloid-Beta-Induced Microglia Polarization

The ability of endocannabinoid (eCB) to change functional microglial phenotype can be explored as a possible target for therapeutic intervention. Since the inhibition of fatty acid amide hydrolase (FAAH), the main catabolic enzyme of anandamide (AEA), may provide beneficial effects in mice model of Alzheimer’s disease (AD)-like pathology, we aimed at determining whether the FAAH inhibitor URB597 might target microglia polarization and alter the cytoskeleton reorganization induced by the amyloid-β peptide (Aβ). The morphological evaluation showed that Aβ treatment increased the surface area of BV-2 cells, which acquired a flat and polygonal morphology. URB597 treatment partially rescued the control phenotype of BV-2 cells when co-incubated with Aβ. Moreover, URB597 reduced both the increase of Rho protein activation in Aβ-treated BV-2 cells and the Aβ-induced migration of BV-2 cells, while an increase of Cdc42 protein activation was observed in all samples. URB597 also increased the number of BV-2 cells involved in phagocytosis. URB597 treatment induced the polarization of microglial cells towards an anti-inflammatory phenotype, as demonstrated by the decreased expression of iNOS and pro-inflammatory cytokines along with the parallel increase of Arg-1 and anti-inflammatory cytokines. Taken together, these data suggest that FAAH inhibition promotes cytoskeleton reorganization, regulates phagocytosis and cell migration processes, thus driving microglial polarization towards an anti-inflammatory phenotype.

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Anti-Inflammatory Effects by Pharmacological Inhibition or Knockdown of Fatty Acid Amide Hydrolase in BV2 Microglial Cells

Cells ◽

10.3390/cells8050491 ◽

2019 ◽

Vol 8 (5) ◽

pp. 491 ◽

Cited By ~ 5

Author(s):

Mikiei Tanaka ◽

Kazuya Yagyu ◽

Scott Sackett ◽

Yumin Zhang

Keyword(s):

Fatty Acid ◽

Inflammatory Cytokines ◽

Fatty Acid Amide Hydrolase ◽

Acid Amide ◽

Pge2 Production ◽

Faah Inhibition ◽

Anti Inflammatory ◽

Amide Hydrolase ◽

Bv2 Microglial Cells ◽

Fatty Acid Amide

Fatty acid amide hydrolase (FAAH) has been recognized as a therapeutic target for several neurological diseases because its inhibition can exert neuroprotective and anti-inflammatory effects by boosting the endogenous levels of N-acylethanolamines. However, previous studies have shown inconsistent results by pharmacological inhibition and genetic deletion of FAAH in response to inflammation. In this study we used two inhibitors, PF3845 and URB597, together with siRNA knockdown to characterize further the effects of FAAH inhibition in BV2 microglial cells. Treatment with PF3845 suppressed lipopolysaccharide (LPS)-induced prostaglandin E2 (PGE2) production, and down-regulated cyclooxygenase-2 and microsomal PGE synthase. PF3845 reduced the expression of pro-inflammatory cytokines but had no effect on the expression of anti-inflammatory cytokines. The anti-inflammatory effects of URB597 were not as potent as those of PF3845. Knockdown of FAAH also suppressed PGE2 production and pro-inflammatory gene expression. Interestingly, FAAH knockdown enhanced expression of anti-inflammatory molecules in both the absence and presence of LPS treatment. The anti-inflammatory effects of FAAH inhibition and knockdown were not affected by the cannabinoid receptor antagonists or the peroxisome proliferator-activated receptor (PPAR) antagonists. Although inhibition and knockdown of FAAH have potent anti-inflammatory effects and possibly lead to the dynamic change of microglial gene regulation, the underlying mechanisms remain to be elucidated.

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