Abstract 3967: CD40-TNF-Receptor Associated Factor (TRAF)6, but not CD40-TRAF2 Interactions in Macrophages and Dendritic Cells Are Crucial in Atherosclerosis
CD40-CD40L interactions play a central role in atherosclerosis. However, the exact cell-type specific CD40-TRAF signaling mechanisms involved are barely known. Here we used CD40−/− mice, CD40-overexpressing mice (CD40-Tg) and a unique mouse model containing TRAF-binding defective CD40 mutants (ie CD40−/− mice with a CD40 transgene under an MHCII promotor with mutated TRAF2 and 6 CD40-binding sites). Mice (n=13–22/group) were crossed with ApoE−/− mice and atherosclerosis was analyzed at 26 wks of age in the aortic arch + branch points. CD40−/− /ApoE−/− mice showed a significant decrease in total plaque area compared to controls (CD40−/−/ApoE−/−:210300±43950 um2 vs ApoE−/−:330900±32500 um2; p=0.034), whereas overexpression of CD40 (CD40-Tg mice) did not affect total plaque area, but resulted in an increased number of initial plaques (CD40-Tg: 1.7±0.3 plaques/arch vs ApoE−/−:0.8±0.1; p=0.004). Plaques of CD40−/−/ApoE−/− mice showed a decrease in CD45+ cells (2.3±0.5% vs 4.4± 0.7%; p=0.019), CD3+ cells (1.3±0.4% vs 4.5±0.9%; p=0.017) and Mac3+ cells (52.1 ±5.4% vs 64.1±6.3%; p=0.046) compared to ApoE−/−mice. Moreover, CD40-T6 signaling, but not CD40-T2 signaling in macrophages and DCs proved to be crucial in atherosclerosis. CD40-T6/ApoE−/− mice show a 89.3% decrease in plaque area compared to controls (CD40-T6/ApoE−/−: 34560±15650 um2 vs CD40-Twt/ ApoE−/−: 323700±46130 um2; p<0.001) and only developed a very limited number of plaques (CD40-T6/ApoE−/−: 0.9±0.2 plaques/arch vs CD40-Twt/ApoE−/−: 3.0±0.2 plaques/arch; P<0.001). Interestingly, no significant differences in plaque area or the number of plaques were observed in CD40-T2/ApoE−/− (p=0.219) and CD40-T26/ApoE−/− mice (p=0.058), suggesting that CD40-T2 interactions partly counteract the effects of CD40-T6 signaling. Plaques of CD40-T6/ApoE−/− and CD40-T2/6/ApoE−/− mice contained less CD45+ (CD40-T6/ ApoE−/−: 0.9±0.4%; p=0.042, CD40-T2/6/ApoE−/−: 1.8±0.4% vs CD40-Twt/ApoE−/−: 5.5±1.0%; p=0.005) and CD3+ (CD40-T6:1.9±0.5%; p=0.032, CD40-T2/6: 2.4±0.7% vs CD40-Twt: 4.1±1.5%; p=0.021) cells. We conclude that atherosclerosis and plaque inflammation is mediated by macrophage and dendritic cell CD40-signaling and that CD40-TRAF6 interactions play a central role.