Potential Role of Scavenger Receptors in Human Mast Cell Cytokine Response to Oxidized LDL

Background: Human atherosclerotic lesions contain mast cells and oxidatively modified low-density lipoprotein particles (oxLDL). Scavenger receptors are cell surface receptors that bind and internalize oxLDL, and they play an important role in macrophage foam cell development, a key event in the initiation and development of atherosclerotic lesions. The purpose of the study was to analyze expression of the most common scavenger receptors in mast cells, and determine whether oxLDL particles can induce them to secrete pro-inflammatory cytokines that are potentially capable of inducing and amplifying atherogenic processes.

Methods: Mast cells were differentiated from human cord blood-derived CD34+ progenitor cells in vitro (CBMC), and their expression of scavenger receptors was analyzed by conventional RT-PCR, flow cytometry and Western blot techniques. Fluorescently-labeled oxLDL was used to investigate LDL internalization by mast cells. Secretion of pro-inflammatory cytokines into the incubation medium and degranulation of the mast cells in response to oxLDL were assayed by ELISA and a colorimetric-enzymatic test for beta-hexosaminidase, respectively.

Results: CBMC expressed mRNA and protein for LOX-1, SR-AI and CD68, but not for CD36, and the expression of LOX-1 and SR-AI was upregulated by incubation of the cells with oxLDL. CBMC internalized oxLDL more efficiently than native LDL, while simultaneous neutralization of CD68, SR-AI and LOX-1 with monoclonal antibodies resulted in reduced oxLDL uptake. Moreover, in response to oxLDL, CBMC showed increased release of β-hexosaminidase,  and a dose-dependent secretion of the pro-inflammatory cytokines IL-8 and MCP-1.

Conclusion: Our results reveal that cultured human mast cells express scavenger receptors that are up-regulated by oxLDL. In atherosclerotic lesions, oxLDL may activate MC to secrete pro-inflammatory cytokines, and so they cause mast cells to act as a cellular link between oxLDL and the inflammatory response in atherosclerosis.