Lipid Receptor G2A-Mediated Signal Pathway Plays a Critical Role in Inflammatory Response by Promoting Classical Macrophage Activation

Macrophage polarization is a dynamic and integral process in tissue inflammation and remodeling. In this study, we describe that lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) plays an important role in controlling inflammatory macrophage (M1) polarization in rodent experimental autoimmune encephalomyelitis (EAE) and in monocytes from multiple sclerosis (MS) patients. Specific inhibition of Lp-PLA(2) led to an ameliorated EAE via markedly decreased inflammatory and demyelinating property of M1. The effects of Lp-PLA(2) on M1 function were mediated by lysophosphatidylcholine, a bioactive product of oxidized lipids hydrolyzed by Lp-PLA(2) through JAK2-independent activation of STAT5 and upregulation of IRF5. This process was directed by the G2A receptor, which was only found in differentiated M1 or monocytes from MS patients. M1 polarization could be inhibited by a G2A neutralizing Ab, which led to an inhibited disease in rat EAE. In addition, G2A-deficient rats showed an ameliorated EAE and an inhibited autoimmune response. This study has revealed a mechanism by which lipid metabolites control macrophage activation and function, modification of which could lead to a new therapeutic approach for MS and other inflammatory disorders.

Automated summary

This study demonstrates the important role of Lp-PLA(2) in controlling inflammatory macrophage polarization in autoimmune encephalomyelitis and multiple sclerosis. Lp-PLA(2) affects M1 function through lysophosphatidylcholine-mediated pathways and G2A receptor guidance, which could potentially lead to new therapeutic approaches for MS and other inflammatory disorders.