Atherosclerosis is a chronic inflammatory process of the vascular endothelium that leads to cardiovascular disease. Generation of oxidized form of LDL (oxLDL) and its uptake by macrophages is an early event in the atherosclerosis. OxLDL also induces an autoimmune response as evidenced by the presence of antibody (IgG) against oxLDL and oxLDL-immune complex (oxLDL-IC) in atherosclerotic lesions in patients and animal model. The titer of autoantibodies against oxLDL is correlated with the progression of atherosclerosis in humans and in the hyperlipidemic mouse model. Therefore, oxLDL-IC could be involved in the inflammatory processes leading to the initiation and progression of atherosclerosis. We have shown that human monocytes adhere to oxLDL-IC coated endothelial cells in vitro and release inflammatory cytokines. This interaction is mediated through a group of cellular receptors called Fc gamma receptors (Fc?R), which bind immune complexes and play a major role in IC-mediated tissue injury in chronic inflammatory disease involving autoantibodies. Interaction of oxLDL-IC with Fc?Rs containing activation motif could initiate an inflammatory response while interaction with Fc?R containing the inhibitory receptor will dampen the inflammatory process. However, the role of Fc?R in initiation and progression of atherosclerosis is not known. We have generated double knock out mice lacking the activating or inhibitory Fc?R, in atherosclerosis prone apoE-/- mice, providing us tools to study the role of Fc?R during atherosclerosis. We have also observed that in addition to its interaction with IC, mouse CD16, a Fc?R can bind oxLDL directly and could have scavenger receptor like activity. Therefore in this proposal we will, (i) determine the role of activating Fc?R during atherosclerosis in vivo, (ii) delineate molecular mechanisms contributing to the attenuated lesions in the activating Fc?R deficient mice, (iii) determine the role of inhibitory Fc?R during atherosclerosis in vivo, and (iv) characterize the SR-like activity of mouse CD16 and determine its functional implications. Completion of this proposed study will significantly advance our understanding the role of Fc?Rs in the progression of atherosclerosis. Further, Our findings would allow for future development of therapeutics to block Fc?R-mediated inflammation with the goal of blocking or preventing the progression of atherosclerosis.
Atherosclerosis remains the leading cause of death in the USA and other Western countries. Completion of this proposed study will significantly advance our understanding the role of Fc?Rs in the lesion development during atherosclerosis. Further, it could allow for designing therapeutics by inhibiting atherogenesis via targeting activating and/or inhibitory Fc?Rs.
|Csányi, Gábor; Feck, Douglas M; Ghoshal, Pushpankur et al. (2017) CD47 and Nox1 Mediate Dynamic Fluid-Phase Macropinocytosis of Native LDL. Antioxid Redox Signal 26:886-901|
|Ng, Hang Pong; Zhu, Xinmei; Harmon, Erin Y et al. (2015) Reduced Atherosclerosis in apoE-inhibitory Fc?RIIb-Deficient Mice Is Associated With Increased Anti-Inflammatory Responses by T Cells and Macrophages. Arterioscler Thromb Vasc Biol 35:1101-12|
|Kaynar, Ata Murat; Yende, Sachin; Zhu, Lin et al. (2014) Effects of intra-abdominal sepsis on atherosclerosis in mice. Crit Care 18:469|
|Burris, Ramona L; Ng, Hang-Pong; Nagarajan, Shanmugam (2014) Soy protein inhibits inflammation-induced VCAM-1 and inflammatory cytokine induction by inhibiting the NF-?B and AKT signaling pathway in apolipoprotein E-deficient mice. Eur J Nutr 53:135-48|
|Harmon, Erin Y; Fronhofer 3rd, Van; Keller, Rebecca S et al. (2014) Anti-inflammatory immune skewing is atheroprotective: Apoe?/?Fc?RIIb?/? mice develop fibrous carotid plaques. J Am Heart Assoc 3:e001232|
|Zhu, Xinmei; Ng, Hang Pong; Lai, Yen-Chun et al. (2014) Scavenger receptor function of mouse Fc? receptor III contributes to progression of atherosclerosis in apolipoprotein E hyperlipidemic mice. J Immunol 193:2483-95|
|Zhang, H; Chen, J; Liu, X et al. (2013) IL-17 induces expression of vascular cell adhesion molecule through signalling pathway of NF-?B, but not Akt1 and TAK1 in vascular smooth muscle cells. Scand J Immunol 77:230-7|
|Owens 3rd, A Phillip; Passam, Freda H; Antoniak, Silvio et al. (2012) Monocyte tissue factor-dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin. J Clin Invest 122:558-68|
|Xie, Chenghui; Ng, Hangpong; Nagarajan, Shanmugam (2011) OxLDL or TLR2-induced cytokine response is enhanced by oxLDL-independent novel domain on mouse CD36. Immunol Lett 137:15-27|
|Ng, Hang Pong; Burris, Ramona L; Nagarajan, Shanmugam (2011) Attenuated atherosclerotic lesions in apoE-Fc?-chain-deficient hyperlipidemic mouse model is associated with inhibition of Th17 cells and promotion of regulatory T cells. J Immunol 187:6082-93|