CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer

In atherosclerosis and Alzheimer’s disease, deposition of the altered-self components oxidized low-density lipoprotein (LDL) and β-amyloid triggers a protracted sterile inflammatory response. Although chronic stimulation of the innate immune system is believed to underlie the pathology of these diseases, the molecular mechanisms of activation remain unclear. Here we show that oxidized LDL and β-amyloid trigger inflammatory signaling through a heterodimer of Toll-like receptors 4 and 6. Assembly of this novel heterodimer is regulated by signals from the scavenger receptor CD36, a common receptor for these disparate ligands. Our results identify CD36-TLR4-TLR6 activation as a common molecular mechanism by which atherogenic lipids and β-amyloid stimulate sterile inflammation and suggest a new model of TLR heterodimerization triggered by co-receptor signaling events.