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

Abstract

Macrophage polarization is a dynamic and integral process in tissue inflammation and remodeling. In this study, we describe that lipoprotein-associated phospholipase A2 (Lp-PLA2) 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-PLA2 led to an ameliorated EAE via markedly decreased inflammatory and demyelinating property of M1. The effects of Lp-PLA2 on M1 function were mediated by lysophosphatidylcholine, a bioactive product of oxidized lipids hydrolyzed by Lp-PLA2 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.

The Patatin–Like Phospholipase Domain Containing Protein 7 Regulates Macrophage Classical Activation through SIRT1/NF-κB and p38 MAPK Pathways

“…Specific PLA2 and LPCAT isoenzymes have been shown to regulate macrophage inflammatory characteristics during differentiation toward M1- or M2-related states. For example, Lp-PLA2 and LPCAT2 promote M1-related characteristics in different in vitro models of macrophage differentiation [ 14 , 32 ]. Conversely, LPCAT3 and group IVC phospholipase A2 have been shown to suppress M1 polarization [ 15 , 16 , 17 , 33 ].…”

“…Several PLA and LPCAT isoforms have been implicated in macrophage polarization. Inhibition of the secreted enzyme lipoprotein-associated phospholipase A 2 (Lp-PLA2) suppressed M1 polarization of human macrophages in vitro [ 14 ]. Depletion of LPCAT3, on the other hand, favored M1 differentiation [ 15 , 16 , 17 ].…”

PLA2G7: a new player in shaping energy metabolism and lifespan

“…As a result, higher amounts of reactive oxygen species (ROS) are produced, driving macrophage activation. 2 The scientists discovered decreased M1 macrophages and a lower expression of pro-inflammatory cytokines characteristic of the immunological phenotype of Pla2g7 mice. However, CD206 + macrophages increased after Pla2g7 deletion.…”

“…Recent studies confirm the relevance of Pla2g7 for shaping the immune phenotype in humans and mice. 2 – 4 Lp-PLA2 (encoded by Pla2g7 ) levels were investigated as a possible biomarker in chronic obstructive pulmonary disease (COPD), a disease indicative for accelerated aging. In the context of chronic inflammation, Lp-PLA2 was increased.…”

“…Spadaro and colleagues’ results underscore the importance of CR in lowering inflammation and validate its influence on life span in agreement with other publications. 2 , 4 Pla2g7 ’s identification as a critical regulatory gene is a significant step forward in understanding the role of adipose tissue metabolism in regulating immune-metabolic effects. Pla2g7 ’s discovery as a key regulator of macrophage polarization should help to better understand inflammatory pathways in adipose tissue.…”