Abstract 14685: RP105, A Cell Surface TLR4 Signaling Regulator, Enhances Atherosclerotic Plaque Formation
Introduction RP105 is a structural homolog of TLR4 and an important regulator of TLR4 signaling. RP105 enhances TLR4 signaling in B-cells while it dampens the TLR4 response on myeloid cells. B-cells are known to increase atherosclerosis independently of antibody production or presence of other leukocytes. A role for RP105 in vascular disease and specifically atherosclerosis is still unknown.
Methods and results Male LDLR-/- mice were irradiated and subsequently received bone marrow from either RP105-/- or wild type control mice. After 6 weeks of recovery the mice were fed a hypercholesterolemic diet for 9 weeks and sacrificed for further analysis (no differences in weight or cholesterol levels). No difference in activation of myeloid cells (DC, macrophages) was found whereas B cell activation was significantly reduced in the RP105-/- chimeras as depicted by the percentage of cell surface bound IgM and CD86 expression on CD19+ B cells. Interestingly, plaque burden in the proximal aorta was significantly attenuated (230±110x103 μm2 vs 131±63 P=0.004) in the RP105-/- chimeras. Furthermore ex vivo stimulation showed that RP105-/- splenocytes are less sensitive to oxLDL or LPS induced (proliferation index; LPS 6.6±2.9 vs 2.1±0.6, oxLDL 5.3±2 vs 1.8±0.3, P<0.05). In agreement with this observation, oxLDL decreased the production of IL10, important for B-cell proliferation, in the RP105-/- chimeras. The atheroprotective effect of RP105 deficiency was independent of total and oxLDL specific antibody levels, likely because RP105 is not expressed by antibody producing plasma cells. Although we could not find a difference in systemic T-cells activation (spleen), we did find a significant reduction in both intimal (13.6±1.9 vs 4.4±0.8, p<0.0001) and perivascular T cell numbers (48.9±15.9 vs 32.0±12.4, p=0.0037).
Conclusion: RP105 enhances plaque formation probably via activation of B-cells.
- © 2011 by American Heart Association, Inc.