Hendrikx Tim, Jeurissen Mike L J, van Gorp Patrick J, Gijbels Marion J, Walenbergh Sofie M A, Houben Tom, van Gorp Rick, Pöttgens Chantal C, Stienstra Rinke, Netea Mihai G, Hofker Marten H, Donners Marjo M P C, Shiri-Sverdlov Ronit
Departments of Molecular Genetics and Pathology, School of Nutrition and Translational Research in Metabolism (NUTRIM) and School for Cardiovascular Diseases, University of Maastricht, The Netherlands.
Departments of Medical Biochemistry and Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, The Netherlands.
FEBS J. 2015 Jun;282(12):2327-38. doi: 10.1111/febs.13279. Epub 2015 Apr 20.
Recent investigations have suggested that inflammasome activation plays an important role during atherosclerosis. Upon activation, the inflammasome induces processing and release of pro-inflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18) via activation of caspase-1/11. Previously, it was shown that complete caspase-1 deficiency is protective against atherosclerosis development. However, while macrophages are the main inflammatory cells involved in atherosclerosis, the exact role of macrophage-specific caspase-1/11 activation during development of cardiovascular disease has never been investigated. We hypothesized that hematopoietic caspase-1/11 deficiency leads to reduced atherosclerosis development. To investigate the specific contribution of hematopoietic caspase-1/11 activation to atherosclerosis development, Ldlr(-/-) mice received a transplant (tp) of wild-type (WT) or caspase-1/11(-/-) bone marrow, to create WT-tp mice and caspase-1/11(-/-) -tp mice, and fed a high-fat, high-cholesterol diet for 12 weeks. Our results showed an increase in anti-inflammatory blood leukocytes in caspase-1/11(-/-) -tp mice compared with WT-tp mice, as indicated by a decreased level of Ly6C(high) monocytes and an increased level of Ly6C(low) monocytes. In line with our hypothesis, hematopoietic deletion of caspase-1/11 resulted in a strong reduction in atherosclerotic plaque size. Furthermore, necrotic core content was dramatically decreased in caspase-1/11(-/-) -tp mice. Our data indicate that hematopoietic caspase-1/11 activation is involved in vascular inflammation and atherosclerosis, and plays an important role in cardiovascular disease progression.
近期研究表明，炎性小体激活在动脉粥样硬化过程中发挥重要作用。激活后，炎性小体通过激活半胱天冬酶-1/11诱导促炎细胞因子白细胞介素1β（IL-1β）和白细胞介素18（IL-18）的加工和释放。此前研究表明，完全缺乏半胱天冬酶-1对动脉粥样硬化发展具有保护作用。然而，虽然巨噬细胞是参与动脉粥样硬化的主要炎症细胞，但巨噬细胞特异性半胱天冬酶-1/11激活在心血管疾病发展过程中的具体作用从未被研究过。我们推测造血细胞半胱天冬酶-1/11缺乏会导致动脉粥样硬化发展减缓。为了研究造血细胞半胱天冬酶-1/11激活对动脉粥样硬化发展的具体作用，Ldlr(-/-)小鼠接受野生型（WT）或半胱天冬酶-1/11(-/-)骨髓移植，以创建WT-tp小鼠和半胱天冬酶-1/11(-/-)-tp小鼠，并给予高脂、高胆固醇饮食12周。我们的结果显示，与WT-tp小鼠相比，半胱天冬酶-1/11(-/-)-tp小鼠中抗炎性血液白细胞增加，表现为Ly6C(高)单核细胞水平降低和Ly6C(低)单核细胞水平升高。与我们的假设一致，造血细胞半胱天冬酶-1/11缺失导致动脉粥样硬化斑块大小显著减小。此外，半胱天冬酶-1/11(-/-)-tp小鼠的坏死核心内容物显著减少。我们的数据表明，造血细胞半胱天冬酶-1/11激活参与血管炎症和动脉粥样硬化，并在心血管疾病进展中起重要作用。
