Despite decades of research, our understanding of the processes controlling late-stage atherosclerotic plaque stability remains poor. A prevailing hypothesis is that reducing inflammation may improve advanced plaque stability, as recently tested in the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) trial, in which post-myocardial infarction subjects were treated with an IL-1β antibody. Here, we performed intervention studies in which smooth muscle cell (SMC) lineage-tracing Apoe-/- mice with advanced atherosclerosis were treated with anti-IL-1β or IgG control antibodies. Surprisingly, we found that IL-1β antibody treatment between 18 and 26 weeks of Western diet feeding induced a marked reduction in SMC and collagen content, but increased macrophage numbers in the fibrous cap. Moreover, although IL-1β antibody treatment had no effect on lesion size, it completely inhibited beneficial outward remodeling. We also found that SMC-specific knockout of Il1r1 (encoding IL-1 receptor type 1) resulted in smaller lesions nearly devoid of SMCs and lacking a fibrous cap, whereas macrophage-selective loss of IL-1R1 had no effect on lesion size or composition. Taken together, these results show that IL-1β has multiple beneficial effects in late-stage murine atherosclerosis, including promotion of outward remodeling and formation and maintenance of an SMC- and collagen-rich fibrous cap.
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We thank the Owens laboratory members for their input. We thank P. Libby, M. Nahrendorf, and P. Swirski for their constructive discussion during the project completion. We thank E. Greene for her assistance in generating the SMC-specific Il1r1 knockout mice, A. Nguyen for performing retro-orbital injections, and M. McCanna for technical support. We thank the University of Pittsburgh Center for Biologic Imaging for their assistance with confocal microscopy. This work was supported by NIH grants R01 HL121008, R01 HL132904, and R01 HL136314 to G.K.O. D.G. was supported by Scientific Development Grant 15SDG25860021 from the American Heart Association. R.A.B. was supported by NIH grant F30 HL136188. B.G.D. was supported by a Predoctoral Fellowship from the American Heart Association (14PRE20380659). C.S.H. was supported by K22HL117917. The generation of the IL1R1fl/fl mice was funded by FP7/EU Project MUGEN (MUGEN LSHG-CT-2005-005203) to W.M. and by MRC research (G0801296) to E.P.
H.G. is a full-time employee of Novartis Pharma AG, Basel.
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Gomez, D., Baylis, R.A., Durgin, B.G. et al. Interleukin-1β has atheroprotective effects in advanced atherosclerotic lesions of mice. Nat Med 24, 1418–1429 (2018). https://doi.org/10.1038/s41591-018-0124-5
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