CD36, a signaling receptor and fatty acid transporter that regulates immune cell metabolism and fate

Abstract

CD36 is a type 2 cell surface scavenger receptor widely expressed in many immune and non-immune cells. It functions as both a signaling receptor responding to DAMPs and PAMPs, as well as a long chain free fatty acid transporter. Recent studies have indicated that CD36 can integrate cell signaling and metabolic pathways through its dual functions and thereby influence immune cell differentiation and activation, and ultimately help determine cell fate. Its expression along with its dual functions in both innate and adaptive immune cells contribute to pathogenesis of common diseases, including atherosclerosis and tumor progression, which makes CD36 and its downstream effectors potential therapeutic targets. This review comprehensively examines the dual functions of CD36 in a variety of immune cells, especially macrophages and T cells. We also briefly discuss CD36 function in non-immune cells, such as adipocytes and platelets, which impact the immune system via intercellular communication. Finally, outstanding questions in this field are provided for potential directions of future studies.

Figure 1.

CD36 functions as both a signal transducer and fatty acid transporter. In response to extracellular signals such as DAMPs, CD36 assembles and interacts with other membrane receptors, including NKA, TLRs, integrins, and tetraspanins, forming distinct signaling complexes. The signaling complexes subsequently relay the signals to various downstream effectors including SFKs, MAPK, AMPK, guanine nucleotide exchange factor Vav, and the NOX family of nicotinamide adenine dinucleotide phosphate oxidases. Activation of these effectors leads to ROS production as well as transcription factor activation, including PPAR-γ and NF-κB. Meanwhile, CD36 also binds with LCFAs and facilitates their transport across the plasma membrane, which impacts fatty acid metabolism and may contribute to activation of the PPAR-γ pathway. The dual functions of CD36 eventually integrate, leading to different cellular responses such as migration, immune activation, differentiation, and cell growth/death.

Figure 2.

CD36 mediates macrophage activation. oxLDL binds to extracellular domains of CD36, which promotes both signaling cascades and lipid uptake. The CD36 cytosolic tail recruits a signalosome complex including SFKs, JNK1/2, and Vav, which is also enhanced by NOX-derived ROS. Both signalosome and ROS (by inhibition of SHP-2) activate focal adhesion kinase (FAK), which leads to dysregulated cytoskeletal dynamics. Meanwhile, extracellular LCFA is transported into the cell via CD36 and then into mitochondria matrix through a series of transport machinery interactions including FABP4, ACSL1, CPT1, and CPT2. LCFA influx to mitochondria facilitates a metabolic switch from OXPHOS to glycolysis, accompanied by a reduction in FAO and increase in ROS production. The signaling cascades and metabolic switch in combination results in NF-κB pathway activation and proatherogenic responses including pro-inflammatory activation, oxLDL uptake, foam cell formation, and trapping of macrophages in the neointima.

Figure 3.

CD36 mediates differential responses in T cell subsets. (A) In T_reg cells, CD36 is upregulated in the TME and facilitates fatty acid (FA) uptake, which subsequently stimulates PPAR-β signaling. Both CD36-mediated fatty acid uptake and PPAR-β signaling support mitochondrial OXPHOS. As a consequence, NAD⁺ is continuously produced from nicotinamide adenine dinucleotide (NADH) through the mitochondrial electron transport chain (ETC). T_reg cells utilize this NAD⁺ pool for metabolism of L-lactate to pyruvate so that they are better adapted to a high-lactate TME and maintain viability and immunosuppressive functions. (B) In TME CD8⁺ T cells, CD36-mediated fatty acid uptake leads to lipid peroxidation and ferroptosis so that these cells are not able to produce cytotoxic cytokines.