IL‐13 induces expression of CD36 in human monocytes through PPARγ activation

Abstract

The class B scavenger receptor CD36 is a component of the pattern recognition receptors on monocytes that recognizes a variety of molecules. CD36 expression in monocytes depends on exposure to soluble mediators. We demonstrate here that CD36 expression is induced in human monocytes following exposure to IL-13, a Th2 cytokine, via the peroxisome proliferator-activated receptor (PPAR)c pathway. Induction of CD36 protein was paralleled by an increase in CD36 mRNA. The PPARc pathway was demonstrated using transfection of a PPARc expression plasmid into the murine macrophage cell line RAW264.7, expressing very low levels of PPARc, and in peritoneal macrophages from PPARc-conditional null mice. We also show that CD36 induction by IL-13 via PPARc is dependent on phospholipase A2 activation and that IL-13 induces the production of endogenous 15-deoxy-D 12,14 -prostaglandin J 2 , an endogenous PPARc ligand, and its nuclear localization in human monocytes. Finally, we demonstrate that CD36 and PPARc are involved in IL-13-mediated phagocytosis of Plasmodium falciparum-parasitized erythrocytes. These results reveal a novel role for PPARc in the alternative activation of monocytes by IL-13, suggesting that endogenous PPARc ligands, produced by phospholipase A2 activation, could contribute to the biochemical and cellular functions of CD36.Leukocyte signaling * These 2 authors contributed equally to this work. IntroductionThe innate immune system protects the host in the early phase of infection. Circulating monocytes and tissue macrophages (Mu) mediate much of this innate immune response [1]. The strategy of recognition in the innate response is mediated by the coordinated action of pathogen-associated molecular patterns and pattern recognition receptors. Scavenger receptors and mannose receptor are important pattern recognition receptors in monocytes/Mu [2,3]. The modulation of the expression of these receptors may be critical in the role of these cells in antigen processing, scavenging, and host defence against pathogens. Several members of the scavenger receptor family, including Mu class A scavenger receptors and CD36, have been identified as receptors for modified lipoproteins on Mu, and their relevance to lipid uptake has been demonstrated in vitro and in vivo [4]. The scavenger receptor CD36, an 88-kDa integral membrane protein, is a class B scavenger receptor expressed on a wide variety of cells, in particular on monocytes and monocytederived Mu [5,6]. CD36 is known as a receptor for the uptake of oxidatively modified low-density lipoprotein (LDL) [7] and is also able to bind anionic phospholipid phosphatidylserine [8]. This scavenger receptor is implicated in the clearance of apoptotic cells [9]. Recently, McGilvray and colleagues [10] described a CD36-dependent nonopsonic phagocytosis of erythrocytes containing P. falciparum, by monocytes and culture-derived Mu, and a decrease in the parasiteinduced TNF secretion by monocytes/Mu. These processes were accentuated by CD36 up-regulation by peroxisome proliferator-acti...

IL-13 Attenuates Gastrointestinal Candidiasis in Normal and Immunodeficient RAG-2−/− Mice via Peroxisome Proliferator-Activated Receptor-γ Activation

“…In conclusion, the present results support our previous in vitro work showing that IL-13 positively regulates macrophage MR surface expression partly by controlling the production of PPAR␥ endogenous ligand, 15d-PGJ 2 , via a cPLA 2 activation both in mouse (6) and in human monocytes (37). It shows the in vivo importance of the nuclear receptor PPAR␥ in the reduction of esophageal and GI candidiasis in immunocompetent and immunodeficient RAG-2 Ϫ/Ϫ mice.…”

“…PPAR␥ is a nuclear receptor initially linked to the regulation of adipogenesis in fat tissue (36). It was previously shown that PPAR␥ can regulate monocyte gene expression and differentiation (16), and that IL-4, and more recently IL-13, induce the expression of the type B scavenger receptor CD36 through PPAR␥ activation (16,(37)(38)(39), hence facilitating the phagocytosis of Plasmodium falciparum-parasitized erythrocytes (37) and to decreasing malaria-induced TNF-␣ secretion (40). In addition to CD36 overexpression, PPAR␥ plays a critical role in the regulation of cholesterol homeostasis by controlling the expression of a network of genes that mediate cholesterol efflux from cells and its transport in plasma.…”

Oxidised LDL up‐regulate CD36 expression by the Nrf2 pathway in 3T3‐L1 preadipocytes

“…Experimental data have revealed the pivotal role exerted by increased PPARc in positively modulating CD36 expression in macrophages in response to different stimuli such as oxLDL [14,23] or cytokines [24]. Thus we evaluated whether the observed up-regulation of CD36 in 3T3-L1 cells was somehow related to oxLDL effects on PPARc activity.…”

12/15-Lipoxygenase metabolites of arachidonic acid activate PPARγ: a possible neuroprotective effect in ischemic brain

“…There is a considerable literature describing the activation of PPAR ␥ by 12/15-LOX metabolites and, thus, the induction of PPAR ␥ itself and target gene expression in multiple cells and tissues ( 28,30,31 ). These data prompted us to examine the possible link of them in brain tissue in the setting of ischemia.…”

“…Another PPAR ␥ agonist, rosiglitazone, also shows potent anti-infl ammatory actions following transient focal ischemia by inhibiting the expression of pro-infl ammatory proteins, myeloperoxidase and intercellular adhesion molecule-1 (ICAM-1), and reduced neutrophil accumulation ( 25 ). Recently, it has been found that 12(S)-and 15-(S)-HETE can function as ligands of PPAR ␥ in the cells derived from outside the CNS (28)(29)(30)(31)(32). However, whether they can regulate PPAR ␥ following brain ischemia is still unknown.…”