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Innate immune cells express various pattern-recognition receptors, among which also Toll-like receptors (TLRs). TLRs occur in atherosclerotic lesions where they are triggered by both exogenous (bacterial and viral pathogens) and endogenous (tissue damage-associated) molecules. Several endogenous TLR activators are described in relation to atherosclerotic disease or ischemia-induced cardiac injury. Experimental animal models have proved the role of TLR endogenous activators in disease initiation and further development. Nowadays, researchers aim to unravel the exact mechanisms involved in the endogenous ligand-dependent TLR signaling and to discover new potential activators, released during pathological conditions such as atherosclerosis and related ischemic manifestations. 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