Abstract 515: Focal Inhibition Of Ip-10 In Atherosclerotic Lesions Potently Inhibits T-cell Influx But Not Plaque Initiation Or Progression
IP-10 is a critical proinflammatory chemokine in atherosclerosis. Complete deletion of IP-10 in ApoE−/− mice was earlier seen to attenuate atherosclerosis by diminishing the influx of effector T cells, thereby correcting the local balance with regulatory T cells. In this study, we have first mapped the IP-10 expression pattern during lesion progression in human carotid arteries by microarray and immunohistochemistry. In line with the microarray data, IP-10 was abundantly expressed in the plaque at all stages of disease progression and by all major cell types (SMCs, Mϕ and endothelial cells). As the IP-10/CXCR3 axis may exert its atherogenic function at a local level by driving chemotaxis to the plaque along an IP-10 gradient, we addressed effects of focal rather than systemic IP-10 blockade. Carotid artery lesions were induced in ApoE−/− mice (n=40) by perivascular collar placement. Lentivirus encoding IP-10 antagonist (LV.IP-10 AT) or GFP control (LV.GFP) entrapped in F127 pluronic gel was administered perivascularly at the common carotid immediately (plaque initiation) or 4 weeks after collar placement (lesion progression), leading to efficient transduction of perivascular tissue. Local CXCR3 antagonism resulted in a sharp decrease in CD3+ cell numbers in the plaque initiation (control 5.5E10−4 ± 1.4E10−4 vs IP-10 AT 2.2E10−4 ± 5.6E10−5 *P= 0.03) and progression study (control 1.6E10−4 ± 3.8E10−5 vs IP-10 AT 5.3E10−5 vs 1.7E10−5 *P= 0.007). Macrophage numbers were also decreased in IP-10AT overexpressing, advanced plaques. Surprisingly, local inhibition of IP-10 did not have any effects on plaque size both in the initiation (control 4.18E104 ± 1.17E104μm2 n=7 vs IP-10 AT 5.3E104 ± 1.02E104μm2 n=9) and progression study (control 7.23E104 ± 1.6E104μm2 n=9 vs IP-10 AT 8.7E104 ± 8.9E103μm2 n=10). Moreover, necrotic core size was significantly enhanced (control 24.35 ± 4.7% vs IP-10 AT 39.62 ± 4.1%; n=9; *P=0.02), and SMC content tended to be decreased in the progression study. In conclusion, our data demonstrate that focal inhibition of IP-10 quenches T-cell recruitment but does not affect plaque initiation or progression, suggesting that atherogenic effects of IP-10 may be attributable to ectopic mobilisation and/or activation of leukocyte subsets.