CD36 and TLR Interactions in Inflammation and Phagocytosis: Implications for Malaria

Abstract

CD36 participates in macrophage internalization of a variety of particles, and has been implicated in inflammatory responses to many of these ligands. To what extent CD36 cooperates with other receptors in mediating these processes remains unclear. Because CD36 has been shown to cooperate with TLR2, we investigated the roles and interactions of CD36 and TLRs in inflammation and phagocytosis. Using Ab-induced endocytosis of CD36 and phagocytosis of erythrocytes displaying Abs to CD36, we show that selective engagement and internalization of this receptor did not lead to proinflammatory cytokine production by primary human and murine macrophages. In addition, CD36-mediated phagocytosis of Plasmodium falciparum malaria-parasitized erythrocytes (PEs), which contain parasite components that activate TLRs, also failed to induce cytokine secretion from primary macrophages. Furthermore, we demonstrate that CD36-mediated internalization did not require TLR2 or the TLR-signaling molecule IRAK4. However, macrophage pretreatment with TLR agonists markedly stimulated particle uptake via CD36. Similarly, PE uptake was unaffected by TLR deficiency, but in wild-type cells was increased by pretreatment with purified P. falciparum glycosylphosphatidylinositols, which activate TLR2. Our findings indicate that CD36 must cooperate with other receptors such as TLRs to participate in cytokine responses. Although purified P. falciparum components activate TLRs, CD36-mediated internalization of intact PEs is not inflammatory. Further, CD36 mediates internalization of particles, including PEs, independently of TLR signaling, but can functionally cooperate with TLRs to enhance internalization.

Genome-wide detection of natural selection in African Americans pre- and post-admixture

“…Since the functional mutations in these genes were not genotyped in this study, we examined the SNPs strongly linked (linkage disequilibrium) with these mutations instead of these mutations themselves. It is well known that rs3211938 is a nonsense mutation c.1389T>G (p.Tyr325X) in CD36 and has been subjected to natural selection because of malaria or some other environmental factors in African (Aitman et al 2000;Omi et al 2003;Erdman et al 2009;Fry et al 2009). We found three SNPs that are highly differentiated between AAF and YRI (Supplemental Table S1) in 7q21 and are strongly linked with rs3211938 (each with r 2 > 0.4 in YRI).…”

“…The 7q21 region harbors two genes: CD36 and SEMA3C. CD36 directly mediates cytoadherence of Plasmodium falciparum parasitized erythrocytes and it binds long chain fatty acids and may function in the transport and/or as a regulator of fatty acid transport (Oquendo et al 1989;Baruch et al 1996;Erdman et al 2009). It was reported that CD36 has been subjected to positive selection for malaria or some unknown selection pressures (Aitman et al 2000;Omi et al 2002Omi et al , 2003Fry et al 2009).…”

Pathogen Associated Molecular Patterns, Pattern Recognition Receptors and Pediatric Sepsis

“…For Plasmodium falciparum, several PAMPs and PRRs have been defined. For example, the scavenger receptor CD36 and TLR2 work in concert to facilitate both internalization of infected erythrocytes and cytokine responses [155]. Also, hemozoin, a byproduct of hemoglobin digestion in malarial parasites serves as another PAMP and activates both NALP3 and TLR9 [156,157].…”

Current Advances in Cerebral Malaria Associated Encephalopathy

“…Among the MyD88-dependent CM-related innate immunity signaling, TLR2 or TLR9 increases susceptibility to CM-related mortality, suggesting that these two TLRs play a critical role in the pathogenesis, and not in protective immunity (Coban, Ishii et al 2007). TLR2 stimulation with P. falciparum glycosylphosphatidylinositol (PfGPI) increases pRBCs uptake and clearance by macrophage as another example of the role of innate immunity responses to malaria (Erdman, Cosio et al 2009). …”