From the Department of Pharmacology (S.E.A., R.P.-G., K.M., R.G., J.A., S.R.B., I.G.S., N.L.).
Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville (S.E.A., R.P.-G., R.G., N.L.).
Arterioscler Thromb Vasc Biol. 2018 May;38(5):1020-1029. doi: 10.1161/ATVBAHA.117.310467. Epub 2018 Mar 29.
Inflammatory macrophages promote the development of atherosclerosis. We have identified the adaptor protein Dab2 (disabled homolog 2) as a regulator of phenotypic polarization in macrophages. The absence of Dab2 in myeloid cells promotes an inflammatory phenotype, but the impact of myeloid Dab2 deficiency on atherosclerosis has not been shown.
To determine the role of myeloid Dab2 in atherosclerosis, Ldlr mice were reconstituted with either Dab2-positive or Dab2-deficient bone marrow and fed a western diet. Consistent with our previous finding that Dab2 inhibits NFκB (nuclear factor κ-light-chain-enhancer of activated B cells) signaling in macrophages, Ldlr mice reconstituted with Dab2-deficient bone marrow had increased systemic inflammation as evidenced by increased serum IL-6 (interleukin-6) levels and increased inflammatory cytokine expression levels in liver. Serum lipid levels were significantly lower in Ldlr mice reconstituted with Dab2-deficient bone marrow, and further examination of livers from these mice revealed drastically increased inflammatory tissue damage and massive infiltration of immune cells. Surprisingly, the atherosclerotic lesion burden in Ldlr mice reconstituted with Dab2-deficient bone marrow was decreased compared with Ldlr mice reconstituted with wild-type bone marrow. Further analysis of aortic root sections revealed increased macrophage content and evidence of increased apoptosis in lesions from Ldlr mice reconstituted with Dab2-deficient bone marrow but no difference in collagen or α-smooth muscle actin content.
Dab2 deficiency in myeloid cells promotes inflammation in livers and atherosclerotic plaques in a mouse model of atherosclerosis. Nevertheless, decreased serum lipids as a result of massive inflammatory liver damage may preclude an appreciable increase in atherosclerotic lesion burden in mice reconstituted with Dab2-deficient bone marrow.
炎性巨噬细胞促进动脉粥样硬化的发展。我们已经确定衔接蛋白 Dab2（失活同源物 2）是巨噬细胞表型极化的调节剂。髓样细胞中 Dab2 的缺失促进炎症表型，但髓样细胞 Dab2 缺失对动脉粥样硬化的影响尚未得到证实。
为了确定髓样细胞 Dab2 在动脉粥样硬化中的作用，用 Dab2 阳性或 Dab2 缺陷的骨髓重建 Ldlr 小鼠，并喂食西方饮食。与我们之前的发现一致，即 Dab2 抑制巨噬细胞中的 NFκB（核因子 κ-轻链增强子的激活 B 细胞）信号，用 Dab2 缺陷的骨髓重建的 Ldlr 小鼠表现出全身炎症增加，表现为血清 IL-6（白细胞介素-6）水平升高和肝脏中炎症细胞因子表达水平升高。用 Dab2 缺陷的骨髓重建的 Ldlr 小鼠的血清脂质水平显著降低，进一步检查这些小鼠的肝脏发现炎症性组织损伤明显增加，免疫细胞大量浸润。令人惊讶的是，与用野生型骨髓重建的 Ldlr 小鼠相比，用 Dab2 缺陷的骨髓重建的 Ldlr 小鼠的动脉粥样硬化病变负担减少。对主动脉根部切片的进一步分析显示，用 Dab2 缺陷的骨髓重建的 Ldlr 小鼠的动脉粥样硬化斑块中的巨噬细胞含量增加，并且有证据表明斑块中的细胞凋亡增加，但胶原蛋白或α-平滑肌肌动蛋白含量没有差异。
髓样细胞中 Dab2 的缺失促进了肝脏炎症和动脉粥样硬化斑块在动脉粥样硬化小鼠模型中的发展。然而，由于大量炎症性肝损伤导致的血清脂质减少，可能会阻止用 Dab2 缺陷的骨髓重建的小鼠的动脉粥样硬化病变负担明显增加。
