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*McLaughlin-Rotman Centre for Global Health, McLaughlin Centre for Molecular Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada;
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada;
Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada;
McGill Faculty of Medicine, Montreal, Quebec, Canada;
¶Department of Biochemistry and Molecular Biology, College of Medicine, Pennsylvania State University, Hershey, Pennsylvania; and
||Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, Toronto General Hospital, Toronto, Ontario, Canada
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.
3 Address correspondence to Dr. Kevin C. Kain, Tropical Disease Unit, Toronto General Hospital, EN 13-214, 200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4. E-mail address: kevin.kain{at}uhn.on.ca
1 This work was supported by a Canadian Institutes of Health Research (CIHR) Team Grant in Malaria (to K.C.K. and S.G.), a CIHR Operating Grant (MT-13721; to K.C.K.), a CIHR MD/PhD Studentship (to L.K.E.), and a CRC Chair in Molecular Parasitology (to K.C.K.).
2 S.G. and K.C.K. contributed equally to this work.
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