Cellular recognition of modified lipoproteins has been linked to the role of scavenger receptors in innate immunity while the cooperation of these receptors remains unclear. We recently showed by fluorescence resonance energy transfer (FRET), that the LPS receptor CD14 is clustered with the integrin associated protein CD47 and the Fc-gamma-receptors CD32 and CD64. Activation by LPS leads to co-association of CD14 with complement receptor 3 (CD11b) and the scavenger receptor CD36. Other ligands to CD14 also induce conformational activation of the cluster while they differ in the pattern of receptors which are recruited. Thus LPS, but not ceramide, induces co-clustering with Toll-like receptor 4 and Fc-gamma-RIIIa (CD16). The effects of both agonists are modulated by the membrane cholesterol content suggesting that rafts are an important determinant.
Interestingly, the same receptor complex which recognizes LPS or ceramide represents a recognition structure for modified lipoproteins and acute phase proteins. Thus, CD36 represents the major binding site for enzymatically modified LDL (E-LDL) and the two Fc-gamma-receptors bind CRP with high affinity. The same FRET approach as well as competition experiments revealed that in acute phase plasma cellular uptake of E-LDL comprises both direct recognition of E-LDL by CD36 and recognition of E-LDL/CRP-complexes by CD32 and CD64. Moreover, CRP accelerates E-LDL induced macrophage foam cell formation.
In conclusion, the cooperation of pattern recognition receptors within rafts represents a mechanism for the differential recognition of exogenous and endogenous ligands. Different patterns of receptor clustering most likely correlate to a ligand specific signal transduction.