Abstract 17759: Bone Morphogenetic Protein 2/4 Stimulate Dendritic and T Cell Inflammatory Responses in Atherosclerosis
Our previous results (Sato et al., Atherosclerosis, 2014) showed that Bone Morphogenetic Proteins (BMP) 2 and 4 and their endogenous antagonist, Gremlin, are overexpressed in human and animal atherosclerotic plaques. Furthermore, plaque vascular smooth muscle cell-produced BMPs induce monocyte chemotaxis through direct BMP receptor II activation. In addition to monocyte recruitment and local macrophage proliferation, dendritic cell (DC)-activated T lymphocytes (TL) appear to be responsible for the growth of atherosclerotic lesions. However, whether BMPs further modulate innate and adaptive immune responses during atherogenesis is yet to be tested. Here, we evaluated the effects of BMPs on DC obtained from ApoE-/- and C57Bl/6 mouse bone marrow precursors. Incubation of DC from C57Bl/6 animals with 10 ng/mL BMP2 or 4 significantly increased (vs. baseline) the production of IFN-γ and IL-12 (+21 and +7 fold, respectively, p<0.005, N=3). While responses to 200 ng/mL LPS were comparable in DC originated from control and ApoE-/- mice, BMP-induced IFN-γ and IL-12 level enhancement was more pronounced in DC from ApoE-/- animals (+2.4 fold vs. C57Bl/6, p<0.05, N=3). Of interest, an opposite effect was seen on IL-10 levels, reduced in those cells following BMP2 or BMP4 administration (-7.5 fold vs. C57Bl/6, p<0.005, N=3). In a separate series of experiments, DC from atherosclerotic plaques were co-cultured with CD4+CD62L+ TL from healthy C57Bl/6 mice. In this system, BMP2 and BMP4 significantly stimulated IFN-γ production (+11 to 15 fold vs. DC alone, p<0.005, N=3). Finally, in preliminary tests, BMP2- or 4-treated ApoE-/- mouse DC expressed higher levels of the antiapoptotic protein BCL-XL. In summary, BMPs induce DC secretion of pro-inflammatory cytokines and potentiate the responses of TL. These effects are more pronounced in ApoE-/- mice and may be related to BMP-facilitated DC survival. Additional studies are underway to better define the importance of BMP signaling on immune modulation in the pathophysiology of atherosclerosis.
Author Disclosures: J.A. Scutti: None.
- © 2014 by American Heart Association, Inc.