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首页> 外文学位 >TLR4/MyD88 Signaling Activates Ultraviolet Irradiation-Induced Apoptosis: Outcomes and Consequences.
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TLR4/MyD88 Signaling Activates Ultraviolet Irradiation-Induced Apoptosis: Outcomes and Consequences.

机译：TLR4 / MyD88信号激活紫外线照射诱导的细胞凋亡：结果和后果。

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摘要

Ultraviolet (UV) irradiation induces DNA damage leading to the accumulation of mutations in epidermal keratinocytes (KC), and immunosuppression, which contribute to development of non-melanoma skin cancers. How the decision to undergo apoptosis is made following UV exposure is not fully understood. We hypothesize that a central mediator of TLR signaling, MyD88, determines cell fate after UV exposure. Survival after UV of immortalized bone marrow-derived macrophages (BMM) and ex vivo peritoneal macrophages (PM) from MyD88 germline-deficient mice (MyD88-/-) was significantly higher vs. wild-type (WT) PM. UV-induced apoptosis in PM and epidermis of MyD88-/- animals was decreased vs. WT. In MyD88-/- PM, decreased cleavage of caspase 3, PARP, and pro-necroptotic protein, RIP1, and a significant increase in pro-inflammatory TNF-alpha, suggest that necroptosis, rather than apoptosis, was initiated. In vivo studies confirm this hypothesis, showing low apoptosis by TUNEL and enhanced histologic inflammation in MyD88-/- skin sections after UV. Considering that MyD88 participates in most TLR signaling pathways, BMM from TLR2-/-, TLR4-/-, TRAM/TRIF -/-, and WT mice were compared for evidence of UV-induced apoptosis. Only TLR4-/- BMM and PM had a similar phenotype to MyD88 -/-, suggesting that the TLR4-MyD88 axis importantly contributes to cell fate decision. We then sought to determine how alteration of this pathway affects the UV-induced damage to critical epidermal cells. In the DNFB hypersensitization model, UV-irradiated, MyD88-/- mice had intact ear swelling, normal IFN-gamma production by T lymphocytes, and higher levels of DNFB-specific IgG2a compared to WT, which were suppressed by UV. The UV-induced emigration of antigen presenting cells from the epidermis was maintained in MyD88 -/- mice, yet UV-induced DNA damage in the local lymph nodes was less pronounced. We then hypothesized that the aforemention preservation of PARP promotes more efficient DNA damage recognition and repair. In support of this hypothesis, human primary KC treated with MyD88 siRNA and epidermal DNA from MyD88-/- and TLR4-/- mice that were UV-irradiated had an increased resolution rate of cyclobutane pyrimidine dimers (CBPD), which can be attenuated by treatment with a PARP-inhibitor. This work provides a strong rationale for future development of topical TLR4 modulating therapies to reduce the risk of UV-induced carcinogenesis.
机译：紫外线（UV）引起DNA损伤，导致表皮角质形成细胞（KC）中突变的积累和免疫抑制，从而促进了非黑素瘤皮肤癌的发展。紫外线照射后如何做出凋亡决定尚不完全清楚。我们假设TLR信号传导的中心媒介，MyD88，决定了紫外线照射后的细胞命运。永生化骨髓来源的巨噬细胞（BMM）和来自MyD88种系缺陷小鼠（MyD88-/-）的离体腹膜巨噬细胞（PM）的紫外线后存活率明显高于野生型（WT）PM。与WT相比，UV诱导的MyD88-/-动物的PM和表皮细胞凋亡减少。在MyD88-/-PM中，半胱天冬酶3，PARP和促坏死性蛋白RIP1的切割减少，促炎性TNF-α显着增加，表明开始了坏死性病变，而不是凋亡。体内研究证实了这一假说，显示紫外线后TUNEL的细胞凋亡低，MyD88-/-皮肤切片的组织学炎症增强。考虑到MyD88参与了大多数TLR信号传导途径，比较了来自TLR2-/-，TLR4-/-，TRAM / TRIF-/-和WT小鼠的BMM，以了解UV诱导的细胞凋亡。只有TLR4-/-BMM和PM具有与MyD88-/-相似的表型，这表明TLR4-MyD88轴对细胞命运的决定至关重要。然后，我们试图确定该途径的改变如何影响紫外线对关键表皮细胞的损害。在DNFB超敏模型中，与WT相比，经紫外线照射的MyD88-/-小鼠耳部肿胀完整，T淋巴细胞正常产生IFN-γ，而WTFB的DNFB特异性IgG2a水平较高，但受到UV抑制。在MyD88-/-小鼠中，紫外线诱导的抗原呈递细胞从表皮中迁移出来，但在局部淋巴结中紫外线诱导的DNA损伤并不明显。然后，我们假设PARP的预先保存促进了更有效的DNA损伤识别和修复。为支持这一假设，用MyD88 siRNA和MyD88-/-和TLR4-/-小鼠经紫外线照射的表皮DNA处理的人类原发性KC环丁烷嘧啶二聚体（CBPD）的拆分率提高，可通过以下方法减弱用PARP抑制剂治疗。这项工作为将来开发局部TLR4调节疗法以降低紫外线诱发的癌变风险提供了有力的依据。

著录项

  • 作者

    Harberts, Erin Marie.;

  • 作者单位

    University of Maryland, Baltimore.;

  • 授予单位 University of Maryland, Baltimore.;
  • 学科 Immunology.;Molecular biology.;Cellular biology.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 104 p.
  • 总页数 104
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 地球物理学;
  • 关键词

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