Background/Purpose: Gout is the most prevalent inflammatory arthritis globally, with rising incidence in both developed and developing regions. It is driven by monosodium urate (MSU) crystal deposition in joints and bursae of hyperuricemic individuals, triggering intense pain and inflammation. Macrophage uptake of MSU crystals activates TLR2/4 signaling, promoting NLRP3 inflammasome formation and NF-κB–mediated pro-inflammatory cytokine production. Penta-O-galloyl-β-D-glucose (PGG), a naturally occurring polyphenol, exhibits anti-inflammatory and anti-proliferative properties. This study investigated PGG’s effects on MSU-induced inflammatory responses and arachidonic acid (AA) metabolism in human PBMCs.

Methods: Human PBMCs were pretreated overnight with 5 µM PGG or 1 µM colchicine, followed by stimulation with 100 µg/mL MSU for either 30 minutes or 24 hours. Cytokine levels (IL-1β, IL-18, TNF-α, IL-6, IL-8, TGFβ) were measured by qPCR and ELISA. Phosphorylated MAPKs (p38, ERK, JNK) were assessed by immunoblotting. Phagocytosis was evaluated using the Vybrant™ Phagocytosis Assay. The fatty acid composition of PBMCs lipids was analyzed by GC/ MS after conversion to methyl esters. The analysis was carried out using a Shimadzu QP2010SE GC/MS equipped with a Supelco Omegawax column (30 m × 0.25 mm × 0.25 μ).

Results: PGG significantly reduced MSU-induced expression of IL-1β, IL-18, TNF-α, IL-6, and IL-8 and increased TGFβ (p< 0.01; n=4), with similar trends observed at the mRNA level. PGG also inhibited phagocytosis of MSU crystals, suggesting reduced upstream TLR signaling. Immunoblotting confirmed that PGG blocked MSU-induced phosphorylation of p38, JNK, and ERK. Furthermore, PGG and colchicine treatment markedly reduced elevated arachidonic acid levels in MSU-treated macrophages.

Conclusion: PGG mitigates MSU-induced inflammation in PBMCs by suppressing cytokine production, phagocytosis, MAPK activation, and arachidonic acid accumulation. Given AA’s pro-inflammatory role as a precursor to eicosanoids. These findings suggest that PGG may represent a promising therapeutic candidate for targeting crystal-induced inflammation in gout.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pgg-suppresses-msu-crystal-triggered-inflammation-and-arachidonic-acid-production-in-pbmcs/