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

Abstract

Acute gouty arthritis is an auto-inflammatory disease caused by the deposition of monosodium urate (MSU) crystals in joints or tissues. Excessive neutrophil recruitment into gouty lesions is a general clinical sign and induces a pain phenotype. Attenuation of successive periods of neutrophil infiltration might be a beneficial approach to achieve therapeutic efficacy. In this study, the activity of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) in attenuation of excess neutrophil infiltration was assessed in gout-induced lesions of BALB/c mice. Neutrophil infiltration in MSU-induced gouty lesions was analyzed using immunohistochemical staining. ELISA and RT-PCR were used to measure attenuation of expression of the major neutrophil chemoattractant, CXC motif chemokine ligand 8 (CXCL8), in a PLAG-treated animal model and in cells in vitro. The animal model revealed massive increased neutrophil infiltration in the MSU-induced gouty lesions, but the PLAG-treated mice had significantly reduced neutrophil numbers in these lesions. The results also indicated that the MSU crystals stimulated a damage-associated molecular pattern that was recognized by the P2Y6 purinergic receptor. This MSU-stimulated P2Y6 receptor was destined to intracellular trafficking. During intracellular endosomal trafficking of the receptor, endosome-dependent signaling provided expression of CXCL8 chemokines for neutrophil recruitment. PLAG accelerated initiation of the intracellular trafficking of the P2Y6 receptor and returning the receptor to the membrane. This process shortened the intracellular retention time of the receptor anchoring endosome and subsequently attenuated endosome-dependent signaling for CXCL8 expression. These study results suggested that PLAG could be used for resolution of acute inflammation induced in gout lesions.

Improving anticancer effect of aPD-L1 through lowering neutrophil infiltration by PLAG in tumor implanted with MB49 mouse urothelial carcinoma

“…In a previous study, we demonstrated the inhibitory effects of PLAG on tumors and tumor metastasis [45,46]. In addition, in severe inflammatory diseases due to excessive neutrophil infiltration, PLAG treatment provided symptom relief by regulating the movement of neutrophils to inflammatory lesions [47][48][49][50][51][52]. The ability of PLAG to regulate neutrophil infiltration and activity in tumor tissue enables the anti-tumor effect of aPD-L1 to be maximized so that cancer patients can make a complete recovery.…”

PLAG alleviates cisplatin-induced cachexia in lung cancer implanted mice

“…Our previous study demonstrated that PLAG effectively alleviated the symptoms of oral mucosal inflammation caused by chemotherapy [ 24 , 25 ]. In addition, PLAG effectively alleviated symptoms of various inflammatory diseases induced by several factors [26] , [27] , [28] , [29] , [30] . In these papers, PLAG effectively regulated intracellular ROS, which prevented tissue damage caused by specific factors and suppressed severe inflammatory responses.…”

“…Our previous study demonstrated that PLAG effectively alleviated the symptoms of oral mucosal inflammation caused by chemotherapy [ 24 , 25 ]. In addition, PLAG effectively alleviated symptoms of various inflammatory diseases such as acute lung injury (ALI), rheumatoid arthritis (RA), hepatitis, and gout [26] , [27] , [28] , [29] , [30] . Cisplatin treatment resulted in rapid weight loss and reduced food intake, which was mitigated in the PLAG co-treatment group.…”

Purinergic Signaling in the Regulation of Gout Flare and Resolution

“…Similarly, the P2Y 1 -like receptor signaling pathway that promotes inflammation may exhibit an inhibitory effect on inflammation. For example, in a gout mouse model, the activation of the P2Y 6 receptors reduces 1-palmitoyl-2-linoleyl-3-acetyl-rac-glycerol-induced neutrophil infiltration, alleviating joint symptoms ( 55 ). Thus, the P2Y receptors play a complex role in inflammatory diseases, either as a friend or foe.…”