Atherosclerosis is a chronic inflammatory disease whose clinical complications, including myocardial infarction (MI) and stroke, are the leading causes of death worldwide. Given the compelling evidence that inflammation plays a key role in development of atherosclerosis, the expectation was that lipid lowering, combined with global suppression of inflammation, would markedly reduce late-stage disease complications. The CANTOS clinical trial testing an IL1 antibody, Canakinumab, provided compelling evidence validating the inflammation hypothesis. However, the drug failed to get FDA approval due to it having modest beneficial effects including no reduction in cardiovascular death (CVD) but a 40% increase in death due to lethal infection. The reasons for the disappointing results of CANTOS are complex but likely were due in part to IL1β antibody treatment inhibiting not only detrimental pro-inflammatory responses, but also evolutionarily conserved beneficial inflammatory processes necessary for injury-repair including formation and maintenance of the ACTA2+ fibrous cap. Consistent with this possibility, we (Gomez et al., 2018 Nature Medicine) previously showed that IL1 receptor signaling in smooth muscle cells (SMC) is required for their investment and retention in the protective fibrous cap, and that treatment of SMC lineage tracing Apoe-/- mice with advanced lesions for 8-weeks with a murine IL1 antibody resulted in multiple detrimental effects including a >50% reduction in SMC number and collagen content within the fibrous cap. Our study is just one of many examples illustrating how pro-inflammatory signaling may have beneficial or detrimental effects on the pathogenesis of atherosclerosis. As such, there is a need to identify more nuanced approaches for inhibiting the adverse effects of chronic inflammation without eliminating beneficial functions essential for tissue repair, immune resistance to pathogens, and inflammation resolution. Studies in this proposal will test the hypothesis that selective inhibition of interleukin 6 (IL-6) trans signaling alone, rather than inhibition of both trans and classic IL-6 receptor (IL-6R) signaling, is not only preferred to avoid immuno-deficiencies, but is also required to see optimal atherosclerosis-protective effects because of offsetting beneficial effects of inhibiting IL-6 trans signaling versus detrimental effects of inhibiting classical IL-6R signaling. We will test this hypothesis as follows. Aim 1 will determine if IL-6 and IL-6R neutralizing antibodies, which inhibit both IL-6 classic and trans signaling, versus the IL6/sIL-6R trap sgp130Fc, which selectively inhibits only IL-6 trans signaling, differentially alter lesion development or pathogenesis including cell-matrix composition and indices of stability. We will do prevention and late stage intervention studies in our novel SMC-endothelial cell (EC) dual lineage tracing Apoe-/-mice, as well as our novel delta CT Ldlr-/-mice which develop adv...