|Nagarajan, Shanumgam -|
Submitted to: Keystone Symposia
Publication Type: Abstract Only
Publication Acceptance Date: November 24, 2009
Publication Date: N/A
Technical Abstract: We have previously shown that oxLDL-immune complexes (oxLDL-IC) binding to Fcgamma receptors (Fc gamma R) expressed on human monocytes leads to induction of pro-inflammatory cytokines. Four classes of mouse Fc gamma Rs have been defined: Fc gamma RI, II, III, and IV. Functionally, Fc gamma Rs can be classified into the activating (Fc gamma RI, III and IV), and the inhibitory (Fc gamma RII) receptors. Fcgamma chain (gamma-chain) is a signaling subunit and necessary for the cell surface expression of all the activating Fc gamma Rs. Studies using gamma-chain deficient mice (deficient in the activating Fc gamma Rs) have shown that mice lacking the activating Fc gamma Rs are resistant to the IC-mediated chronic inflammatory diseases. The presence of anti-oxLDL IgG in hyperlipidemic conditions is well documented in human and animal models. We hypothesize that oxLDL-IC interaction with the activating Fc gamma R contributes to the progression of atherosclerosis. To address this hypothesis we generated apoE-gamma-chain double knockout (apoE-gamma chain DKO) mice. Atherosclerotic lesions in aortic sinus and enface analyses of aortic tree showed about 50% reduction in lesions in apoE-gamma- chain DKO mice compared to apoE KO mice. Plasma cholesterol and inflammation marker SAA levels were similar in apoE KO and apoE-gamma-chain DKO mice. Interestingly, T cell analyses revealed that gamma-chain deficiency on hematopoietic cells induced IL-10, IL-4, and TGF-beta expression and lower levels of IFN-gamma and IL-17. These findings suggest activating Fc gamma Rs contribute to the progression by promoting Th1 responses.