NLRP3 mediates atheromatous plaque macrophage proliferation

Abstract

Abstract Background Macrophage accumulation in atherosclerotic plaques drives disease progression largely dependent on in situ proliferation. We previously reported that systemic cholesterol lowering or reduced modified lipoprotein uptake supress atheromatous plaque macrophage proliferation. In this work we investigate the intracellular mediators of macrophage proliferation. Methods and results Macrophages deficient in scavenger receptors CD36 or Msr1 and impaired in cholesterol-rich lipoprotein uptake, proliferated less compared to control macrophages in the same plaque exposed to the same lipid levels in a LDLR-deficient bone marrow irradiation mixed chimera model. Proliferation of plaque macrophages deficient in the intracellular cholesterol sensor LXR was not impaired, however. As modified LDL uptake can activate the NLRP3 inflammasome, we generated mixed bone marrow knockout chimeras for components of the inflammasome. NLRP3 but not Caspase-1 or interleukin-1 receptor deficient macrophages proliferated 35% less compared to NLRP3-expressing macrophages in the same plaque in vivo. These results were confirmed in NLRP3-deficient oxLDL stimulated macrophages in vitro. In line, NLRP3 inhibition of human carotid artery plaque cultures suppressed human plaque macrophage proliferation and reduced inflammasome-dependent IL-1b secretion. However, IL-1b supplementation did not restore local macrophage proliferation in accord with our findings in IL-1 receptor deficient murine plaque macrophages. Conclusion We identified a novel role for NLRP3, independent of the canonical Caspase-1–IL-1b inflammasome pathway, in mediating macrophage proliferation in atherosclerotic plaques in mice and men representing a druggable target. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): DFG