Sager Hendrik B, Heidt Timo, Hulsmans Maarten, Dutta Partha, Courties Gabriel, Sebas Matthew, Wojtkiewicz Gregory R, Tricot Benoit, Iwamoto Yoshiko, Sun Yuan, Weissleder Ralph, Libby Peter, Swirski Filip K, Nahrendorf Matthias
From Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, Boston, MA (H.B.S., T.H., M.H., P.D., G.C., M.S., G.R.W., B.T., Y.I., Y.S., R.W., F.K.S., M.N.); Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.); and Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.L.).
Circulation. 2015 Nov 17;132(20):1880-90. doi: 10.1161/CIRCULATIONAHA.115.016160. Epub 2015 Sep 10.
Myocardial infarction (MI) is an ischemic wound that recruits millions of leukocytes. MI-associated blood leukocytosis correlates inversely with patient survival, yet the signals driving heightened leukocyte production after MI remain incompletely understood.
With the use of parabiosis surgery, this study shows that soluble danger signals, among them interleukin-1β, increase bone marrow hematopoietic stem cell proliferation after MI. Data obtained in bone marrow reconstitution experiments reveal that interleukin-1β enhances hematopoietic stem cell proliferation by both direct actions on hematopoietic cells and through modulation of the bone marrow's hematopoietic microenvironment. An antibody that neutralizes interleukin-1β suppresses these effects. Anti-interleukin-1β treatment dampens the post-MI increase in hematopoietic stem cell proliferation. Consequently, decreased leukocyte numbers in the blood and infarct reduce inflammation and diminish post-MI heart failure in ApoE(-/-) mice with atherosclerosis.
The presented insight into post-MI bone marrow activation identifies a mechanistic target for muting inflammation in the ischemically damaged heart.
心肌梗死(MI)是一种缺血性损伤,会募集数百万白细胞。与MI相关的血白细胞增多与患者生存率呈负相关,但MI后驱动白细胞生成增加的信号仍未完全了解。
通过联体共生手术,本研究表明可溶性危险信号,其中包括白细胞介素-1β,在MI后会增加骨髓造血干细胞增殖。骨髓重建实验获得的数据显示,白细胞介素-1β通过对造血细胞的直接作用以及对骨髓造血微环境的调节来增强造血干细胞增殖。一种中和白细胞介素-1β的抗体可抑制这些作用。抗白细胞介素-1β治疗可抑制MI后造血干细胞增殖的增加。因此,在患有动脉粥样硬化的ApoE(-/-)小鼠中,血液和梗死灶中白细胞数量的减少可减轻炎症并减少MI后心力衰竭。
对MI后骨髓激活的深入了解确定了一个减轻缺血性损伤心脏炎症的机制靶点。