1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol ameliorates arthritic joints through reducing neutrophil infiltration mediated by IL-6/STAT3 and MIP-2 activation

Abstract

The pathogenesis of rheumatoid arthritis (RA) has been implicated neutrophil extracellular traps (NETs) formation which could generate autoantigen. Neutrophil contributes to initiate and maintain the inflammatory process in the joint. In this study, we show that 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) decreases neutrophil migration by regulating the activity of STAT3, a regulator of IL-6 and MIP-2 expression. PLAG caused a decrease in IL-6 production in the RAW264.7 macrophage cell line and in rheumatoid arthritis–fibroblast-like synoviocytes via the regulation of STAT3 signaling without affecting NF-κB signaling. In a mouse model of collagen-induced arthritis (CIA), arthritic symptoms were recapitulated, with increased IL-6 level in the synovium, and PLAG treatment restored IL-6 to a level comparable to that achieved with commercial therapeutics (such as Remicade or methotrexate). Staining of joint tissue with neutrophil-specific antibody showed that PLAG significantly reduced the infiltration of neutrophils into the joint synovium of CIA mice. The inhibitory effect of PLAG on IL-6/STAT3 or MIP-2 signaling also reduced the migration of differentiated neutrophils in vitro. Therefore, PLAG inhibits the infiltration of destructive neutrophils into inflammatory sites, and can be utilized as a potent therapeutic agent for the treatment of sustained inflammation and joint destruction.

Mitigating Effects of 1-Palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) on Hematopoietic Acute Radiation Syndrome after Total-Body Ionizing Irradiation in Mice

“…As reported elsewhere, it has been shown that PLAG is an effective therapeutic candidate in different inflammatoryassociated diseases, such as rheumatoid arthritis, atopic dermatitis, asthma and hepatitis (20,(34)(35)(36). In addition, the therapeutic efficacy of PLAG has been demonstrated in chemotherapy and radiation-induced oral mucositis in hamster and mouse models, through the effective attenuation of neutrophil infiltration into cheek pouches and tongues and a decrease in inflammatory cytokines (37).…”

PLAG Exerts Anti-Metastatic Effects by Interfering with Neutrophil Elastase/PAR2/EGFR Signaling in A549 Lung Cancer Orthotopic Model

“…The anti-metastasis effect of PLAG might be achieved by the disruption of PAR2 signaling, which mediates tumor cell activation in the presence of neutrophil elastase. PLAG has been studied in various inflammatory diseases including chemotherapy-induced neutropenia (CIN), chemo/radiation-induced oral mucositis (CRIOM), and rheumatoid arthritis (RA) [33][34][35]. Our results suggest that PLAG as a novel candidate molecule for the inhibition or retardation of tumor metastasis.…”

“…The 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) is present in the antlers of the Sika deer and can be synthesized from glycerol, palmitic acid, and linoleic acid [32]. PLAG was recently shown to reduce the gemcitabine-induced neutropenia, oral mucositis and arthritis by modulating neutrophil movement [33][34][35]. There have not yet been any studies to determine if PLAG has the potential to control cancer progression by regulating neutrophil infiltration.…”

1-Palmitoyl-2-Linoleoyl-3-Acetyl-rac-Glycerol (PLAG) Mitigates Monosodium Urate (MSU)-Induced Acute Gouty Inflammation in BALB/c Mice

“…It is chemically synthesized from glycerol, palmitic acid, and linoleic acid (28). PLAG reduces lipopolysaccharideinduced macrophage inflammatory protein 2 (MIP-2) and CXCL8 secretion (29). PLAG improves hepatic injury in concanavalin A-treated mice (9), and gemcitabine-induced neutropenia (30,31) and oral mucositis in hamster and mouse models (32), via modulation of neutrophil migration.…”