Uptake of oxLDL and IL-10 Production by Macrophages Requires PAFR and CD36 Recruitment into the Same Lipid Rafts

Abstract

Macrophage interaction with oxidized low-density lipoprotein (oxLDL) leads to its differentiation into foam cells and cytokine production, contributing to atherosclerosis development. In a previous study, we showed that CD36 and the receptor for platelet-activating factor (PAFR) are required for oxLDL to activate gene transcription for cytokines and CD36. Here, we investigated the localization and physical interaction of CD36 and PAFR in macrophages stimulated with oxLDL. We found that blocking CD36 or PAFR decreases oxLDL uptake and IL-10 production. OxLDL induces IL-10 mRNA expression only in HEK293T expressing both receptors (PAFR and CD36). OxLDL does not induce IL-12 production. The lipid rafts disruption by treatment with βCD reduces the oxLDL uptake and IL-10 production. OxLDL induces co-immunoprecipitation of PAFR and CD36 with the constitutive raft protein flotillin-1, and colocalization with the lipid raft-marker GM1-ganglioside. Finally, we found colocalization of PAFR and CD36 in macrophages from human atherosclerotic plaques. Our results show that oxLDL induces the recruitment of PAFR and CD36 into the same lipid rafts, which is important for oxLDL uptake and IL-10 production. This study provided new insights into how oxLDL interact with macrophages and contributing to atherosclerosis development.

Feed-Forward Reciprocal Activation of PAFR and STAT3 Regulates Epithelial–Mesenchymal Transition in Non–Small Cell Lung Cancer

“…This axis activates expression of Th17 cell cytokines, such as IL17, IL23, or IL6 and synergizes with CD36 to enhance the IL10 secretion in macrophages (47,48). Considering that immune cells in cancer microenvironment have important functions in cancer progression through producing many cytokines (49,50), the PAF/PAFR axis in cancer microenvironment, may also influence cancer growth and metastasis via regulating cytokine secretion in immune cells.…”

The role of CD36 receptor in the pathogenesis of atherosclerosis

“…16 By contrast, the blockage of CD36 reduced the secretion of IL-1β, IL-6 and IL-8 and foam cell formation in human macrophages. 17 Based on the results of the above studies, it can be concluded that reduction of CD36 receptor expression on macrophages prevents the development of atherosclerosis.…”

“…Rios et al showed that blocking CD36 and PAFR (Platelet Activating Factor) decreases oxLDL uptake and IL-10 production by macrophages as well as PAFR and CD36 are colocalized in human atherosclerotic plaques. 16 They found that uptake of oxLDL and IL-10 production induced by oxLDL increasing the phosphorylation of PPARγ. This results in reduced transcription of CD36 mRNA.…”

“…In PXR-humanized ApoE deficient mice, exposure to bisphenol A significantly increased the atherosclerotic lesion area in the aortic root and brachiocephalic artery as well as increased CD36 expression and lipid accumulation in macrophages. 38 This suggests that deficiency of PXR reduces the risk of atherosclerosis development which may be due to decreased CD36 expression and reduced lipid uptake in macrophages. 37 Méndez-Barbero et al found that CD36 expression also depends on RCAN1 (regulator of calcineurin 1 activity).…”

Platelet-Activation Factor Receptor Induces Interleukin 10 Production through STAT3 Activation in Dendritic Cells

“…Macrophages have high expression of F4/80, CD36, and TLRs, whereas DCs present high expression of MHCII, costimulatory molecules (CD80, CD86, CD40), TLRs, and have properties of antigen presenting cells higher than macrophages. We showed before that CD36 is a scavenger receptor able to assemble with PAFR in lipid rafts to interact with PAFR ligands and enhance the production of IL-10 by macrophages [17,31]. These effects were abrogated in the presence of PAFR antagonists or anti-CD36 blocking antibody [17].…”