SummaryWithinthe chemokine familyofsmallchemotacticpolypeptides CX3CL1 (fractalkine)and CXCL16 (SR-PSOX)are exceptional in that theya re synthesizeda st ransmembranem oleculesa nd canbecleaved from the cell surfacetoproduce asolublechemoattractant. As transmembrane molecules on the surfaceo f endothelialcells,CX3CL1 and CXCL16 can interact with their receptors CX3CR1a nd CXCR6, respectively, which aree xpressedonleukocyte subtypes.This interactionleads to cell-cell adhesion that is resistant to shearf orces. Tr ansmembrane CX3CL1 and CXCL16 areconstitutivelyshedfromthe cell surfaceb yt he activity of ad isintegrin and metalloproteinase (ADAM) 10,and cleavage canberapidly enhanced by activation of thec loselyr elatede nzyme ADAM17.This cleavage leads to thedownregulationofadhesivepropertiesand mayevenresult in the detachment of boundcells.Functionally,both chemokines Keywords Chemokines, adhesion, metalloproteinases,s hedding, atherosclerosis appear to exerth omeostatic and inflammatorya ctivities. Basal expression of CX3CL1o rC XCL16 mayb er elevant forp ositioninga nd survival of tissue-homingl eukocytes. Upregulated expression is found under inflammatory conditions such as atherosclerosis whereCXCL16 mayhaveadual functionbyacting as an adhesion molecule and by promoting uptake of oxidized LDLasascavenger receptor.Accumulatingevidence from knockout mice and genetic polymorphisms in humans pointstowards ad ifferential contribution of CX3CL1 and CXCL16 in atherosclerosis, wheres hedding mays erve to furtherr egulate their biologicalfunctions.Smallmoleculesthat block eitherthe receptors or the shedding enzymesoftransmembranechemokinesn eed to be tested in animal modelso fv ascular inflammation.