Fragments of Genomic DNA Released by Injured Cells Activate Innate Immunity and Suppress Endocrine Function in the Thyroid
Fragments of Genomic DNA Released by Injured Cells Activate Innate Immunity and Suppress Endocrine Function in the Thyroid
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DOI：
10.1210/en.2010-1132
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发表时间：
2011-04-01
期刊：
影响因子：
4.8
通讯作者：
Suzuki, Koichi
中科院分区：
文献类型：
--
作者：
Kawashima, Akira;Tanigawa, Kazunari;Suzuki, Koichi
先天性和获得性免疫应答的激活，其可由感染、炎症或组织损伤诱导，可影响自身免疫的发展。虽然双链DNA（dsDNA）刺激细胞已显示激活免疫应答，但在无菌细胞损伤的背景下释放的自身基因组DNA片段的作用尚不清楚。使用培养的甲状腺细胞，我们表明，细胞损伤促使基因组DNA释放到胞质溶胶中，这与I型干扰素，炎性细胞因子和趋化因子的产生有关。抗原加工和呈递给淋巴细胞所必需的分子也在甲状腺细胞中因损伤而被诱导。dsDNA强烈抑制钠/碘同向转运体的表达和放射性碘摄取。为了鉴定负责感测胞质dsDNA的分子，我们通过质谱法直接鉴定了结合dsDNA琼脂糖柱的细胞蛋白。我们的分析确定了组蛋白H2 B，这是以前被证明是一个必不可少的因素，介导激活的先天免疫诱导的dsDNA。使用特异性小干扰RNA敲低组蛋白H2 B可消除细胞损伤诱导的先天免疫激活，并增加钠/碘同向转运体表达。这些结果表明，细胞损伤释放的基因组DNA片段被染色体外组蛋白H2 B识别，这导致甲状腺细胞中参与先天性和获得性免疫应答的基因的激活和甲状腺功能的抑制。这些结果表明，无菌性甲状腺损伤，在没有感染的情况下，可能足以触发自身免疫反应，并诱导甲状腺功能障碍。（内分泌学152：1702-1712，2011）
Activation of innate and acquired immune responses, which can be induced by infection, inflammation, or tissue injury, may impact the development of autoimmunity. Although stimulation of cells by double-stranded DNA (dsDNA) has been shown to activate immune responses, the role of self-genomic DNA fragments released in the context of sterile cellular injury is not well understood. Using cultured thyroid cells, we show that cell injury prompts the release of genomic DNA into the cytosol, which is associated with the production of type I interferons, inflammatory cytokines, and chemokines. Molecules necessary for antigen processing and presentation to lymphocytes are also induced in thyroid cells by injury. dsDNA strongly suppressed the expression of sodium/iodide symporter and radio-iodine uptake. To identify molecules responsible for sensing cytosolic dsDNA, we directly identified the cellular proteins that bound a dsDNA Sepharose column by mass spectrometry. Our analysis identified histone H2B, which was previously demonstrated to be an essential factor that mediates the activation of innate immunity induced by dsDNA. Knock down of histone H2B using specific small interfering RNA abolished cell injury-induced innate immune activation and increased sodium/iodide symporter expression. These results indicate that genomic DNA fragments released by cell injury are recognized by extrachromosomal histone H2B, which results in the activation of genes involved in both innate and acquired immune responses in thyroid cells and suppression of thyroid function. These results suggest that sterile thyroid injury, in the absence of infection, may be sufficient to trigger autoimmune reaction and to induce thyroid dysfunction. (Endocrinology 152: 1702-1712, 2011)