Expansion of necrotic core and shedding of Mertk receptor in human carotid plaques: a role for oxidized polyunsaturated fatty acids?

Expansion of necrotic core (NC), a major feature responsible for plaque disruption, is likely the consequence of accelerated macrophage apoptosis coupled with defective phagocytic clearance (efferocytosis). The cleavage of the extracellular domain of Mer tyrosine kinase (Mertk) by metallopeptidase domain17 (Adam17) has been shown to produce a soluble Mertk protein (sMer), which can inhibit efferocytosis. Herein, we analysed the expression and localization of Mertk and Adam17 in the tissue around the necrotic core (TANC) and in the periphery (P) of human carotid plaques. Then we studied the mechanisms of NC expansion by evaluating which components of TANC induce Adam17 and the related cleavage of the extracellular domain of Mertk. We studied 97 human carotid plaques. The expression of Mertk and Adam17 was found to be higher in TANC than in P (P 0.001). By immunohistochemistry, Mertk was higher than Adam17 in the area of TANC near to the lumen (P 0.01) but much lower in the area close to NC (P 0.01). The extract of this portion of TANC increased the expression (mRNA) of Adam17 and Mertk (P 0.01) in macrophage-like THP-1 cells but it also induced the cleavage of the extracellular domain of Mertk, generating sMer in the medium (P 0.01). This effect of TANC extract was most evoked by its content in F-2-isoprostanes, hydroxyoctadecadienoic acids, and hydroxytetraenoic acids. Some oxidized derivatives of polyunsaturated fatty acids contained in TANC of human carotid plaques are strong inducers of Adam17, which in turn leads to the generation of sMer, which can inhibit efferocytosis.