Monocyte-to-macrophage differentiation: synthesis and secretion of a complex extracellular matrix.
Monocyte-to-macrophage differentiation: synthesis and secretion of a complex extracellular matrix.
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单核细胞向巨噬细胞分化：复杂细胞外基质的合成和分泌。
DOI：
10.1074/jbc.m111.324988
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发表时间：
2012-04-20
期刊：
影响因子：
--
通讯作者：
Wight TN
中科院分区：
文献类型：
--
作者：
Chang MY;Chan CK;Braun KR;Green PS;O'Brien KD;Chait A;Day AJ;Wight TN
背景：巨噬细胞的分化伴随着独特的细胞外基质分子的表达。结果：单核细胞向巨噬细胞的转变涉及到serglycin、TSG-6、透明质酸和versican的选择性表达，以及α-胰蛋白酶抑制剂和淀粉样前体蛋白复合物的形成。结论：分化巨噬细胞合成和分泌新的ECM分子。意义：这些ECM分泌产物可能在巨噬细胞分化和动脉粥样硬化的发病机制中发挥作用。虽然单核细胞和巨噬细胞来源的分子已知会促进细胞外基质（ECM）的破坏和不稳定，但很少有人认识到它们也能合成有助于ECM形成、稳定和功能的分子。我们已经鉴定和表征了蛋白聚糖和相关蛋白的合成，其中一些以前不知道与巨噬细胞有关。用肉豆酸酯phorbol处理诱导分化的THP-1单核细胞的[35S]硫酸盐和35S反式氨基酸放射标记培养基的蛋白多糖提取物在软骨素ABC裂解酶消化后显示出三种主要蛋白，分别为~ 25、90和100 kDa。单核细胞以25 kda蛋白为主，巨噬细胞以90和100 kda蛋白为主。串联质谱鉴定(i) 25 kda的核心蛋白为serglycin， （ii） 90 kda的核心蛋白为α-抑制剂重链2 (i -α ihc2), (iii) 100 kda的核心蛋白为淀粉样蛋白前体样蛋白2 （APLP2）。分化还与(i) tnf刺激的基因-6（重链介导的基质稳定的重要辅助因子）mRNA的500倍增加有关；（ii）负责透明质酸合成的HAS2 mRNA增加了约800倍；（iii）与透明质酸相互作用的versican mRNA增加3倍。生物化学证据也显示了i - α ihc2 -APLP2复合物的存在，人类动脉粥样硬化病变的免疫组织化学染色显示了巨噬细胞对APLP2和i - α ihc2的相似染色模式，而serglycin则定位于潜在的富含糖胺聚糖的区域。这些发现表明，巨噬细胞可以合成许多参与ECM形成和功能的分子，提示这些分子在动脉粥样硬化发生过程中巨噬细胞的分化中发挥了新的作用。
Background: Macrophage differentiation is accompanied by expression of unique extracellular matrix molecules. Results: Monocyte-to-macrophage transition involves selective expression of serglycin, TSG-6, hyaluronan, and versican and the formation of inter-α-trypsin inhibitor and amyloid-like precursor protein complexes. Conclusion: Differentiating macrophages synthesize and secrete novel ECM molecules. Significance: These ECM secretory products likely play a role in macrophage differentiation and the pathogenesis of atherosclerosis. Although monocyte- and macrophage-derived molecules are known to promote extracellular matrix (ECM) disruption and destabilization, it is less appreciated that they also synthesize molecules contributing to ECM formation, stabilization, and function. We have identified and characterized the synthesis of proteoglycans and related proteins, some not previously known to be associated with macrophages. Proteoglycan extracts of [35S]sulfate- and 35S-trans amino acid-radiolabeled culture media from THP-1 monocytes induced to differentiate by treatment with phorbol myristate acetate revealed three major proteins of ∼25, 90, and 100 kDa following chondroitin ABC lyase digestion. The 25-kDa protein was predominant for monocytes, whereas the 90- and 100-kDa proteins were predominant for macrophages. Tandem mass spectrometry identified (i) the 25-kDa core protein as serglycin, (ii) the 90-kDa core protein as inter-α-inhibitor heavy chain 2 (IαIHC2), and (iii) the 100-kDa core as amyloid precursor-like protein 2 (APLP2). Differentiation was also associated with (i) a >500-fold increase in mRNA for TNF-stimulated gene-6, an essential cofactor for heavy chain-mediated matrix stabilization; (ii) a >800-fold increase in mRNA for HAS2, which is responsible for hyaluronan synthesis; and (iii) a 3-fold increase in mRNA for versican, which interacts with hyaluronan. Biochemical evidence is also presented for an IαIHC2-APLP2 complex, and immunohistochemical staining of human atherosclerotic lesions demonstrates similar staining patterns for APLP2 and IαIHC2 with macrophages, whereas serglycin localizes to the underlying glycosaminoglycan-rich region. These findings indicate that macrophages synthesize many of the molecules participating in ECM formation and function, suggesting a novel role for these molecules in the differentiation of macrophages in the development of atherosclerosis.