PAFR in adipose tissue macrophages is associated with anti-inflammatory phenotype and metabolic homoeostasis

Author(s)

Filgueiras, Luciano Ribeiro ^[1] ; Koga, Marianna Mainardi ^[1] ; Quaresma, Paula G. ^[2] ; Ishizuka, Edson Kiyotaka ^[1] ; Montes, Marlise B. A. ^[1] ; Prada, Patricia O. ^{[2, 3]} ; Saad, Mario J. ^[2] ; Jancar, Sonia ^[1] ; Rios, Francisco J. ^[4]

Affiliation

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo - Brazil

^[2] State Univ Campinas UNICAMP, Dept Internal Med, Campinas, SP - Brazil

^[3] State Univ Campinas UNICAMP, Sch Appl Sci, Limeira, SP - Brazil

^[4] Univ Glasgow, BHF Glasgow Cardiovasc Res Ctr, Inst Cardiovasc & Med Sci, 126 Univ Pl, Glasgow G12 8TA, Lanark - Scotland

• Document type: Journal article
• Source: Clinical Science; v. 130, n. 8, p. 601-612, APR 1 2016.
• Web of Science Citations: 5

Abstract

Metabolic dysfunction is associated with adipose tissue inflammation and macrophage infiltration. PAFR (platelet-activating factor receptor) is expressed in several cell types and binds to PAF (platelet-activating factor) and oxidized phospholipids. Engagement of PAFR in macrophages drives them towards the anti-inflammatory phenotype. In the present study, we investigated whether genetic deficiency of PAFR affects the phenotype of ATMs (adipose tissue macrophages) and its effect on glucose and insulin metabolism. PARFKO (PAFR-knockout) and WT (wild-type) mice were fed on an SD (standard diet) or an HFD (high-fat diet). Glucose and insulin tolerance tests were performed by blood monitoring. ATMs were evaluated by FACS for phenotypic markers. Gene and protein expression was investigated by real-time reverse transcription-quantitative PCR and Western blotting respectively. Results showed that the epididymal adipose tissue of PAFRKO mice had increased gene expression of Ccr7, Nos2, Il6 and Il12, associated with pro-inflammatory mediators, and reduced expression of the anti-inflammatory Il10. Moreover, the adipose tissue of PAFRKO mice presented more pro-inflammatory macrophages, characterized by an increased frequency of F4/80(+)CD11c(+) cells. Blood monocytes of PAFRKO mice also exhibited a pro-inflammatory phenotype (increased frequency of Ly6C(+) cells) and PAFR ligands were detected in the serum of both PAFRKO and WT mice. Regarding metabolic parameters, compared with WT, PAFRKO mice had: (i) higher weight gain and serum glucose concentration levels; (ii) decreased insulin-stimulated glucose disappearance; (iii) insulin resistance in the liver; (iv) increased expression of Ldlr in the liver. In mice fed on an HFD, some of these changes were potentiated, particularly in the liver. Thus it seems that endogenous ligands of PAFR are responsible for maintaining the anti-inflammatory profile of blood monocytes and ATMs under physiological conditions. In the absence of PAFR signalling, monocytes and macrophages acquire a pro-inflammatory phenotype, resulting in adipose tissue inflammation and metabolic dysfunction. (AU)

• FAPESP's process: 13/15719-0 - Association of receptors for lipid mediators with PRRs in macrophages and dendritic cells
• Grantee: Sônia Jancar
• Support Opportunities: Research Projects - Thematic Grants