Endogenous Reverse Transcriptase Inhibition Attenuates TLR5-Mediated Inflammation.
Endogenous Reverse Transcriptase Inhibition Attenuates TLR5-Mediated Inflammation.
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转座元件 (TE) 是可移动的基因组序列，涵盖大约 50% 的人类基因组。 1 类 TE 或“逆转录转座子”通过产生 RNA 中间体进行动员，然后将其反转录形成能够重新插入基因组的互补 DNA (cDNA) 分子。虽然 TE 传统上被沉默以维持基因组完整性，但对免疫刺激信号（例如微生物提供的信号）的识别会极大地改变宿主转录，从而诱导 TE 的差异表达。新出现的证据表明，TE cDNA 的诱导产生并不是一种惰性现象，而是被宿主免疫所利用，通过激动内在的抗病毒受体来促进宿主和微生物群成分之间的交流。在这里，我们证明用脂多糖（LPS）免疫刺激Toll样受体4（TLR4）和用细菌鞭毛（FLA）免疫刺激TLR5可以改变逆转录转座子的表达，例如人内源性逆转录病毒（HERV）和长散布核元件（LINE）。接下来，我们证明逆转录酶抑制剂 (RTi) 递送可改善单核细胞系 (THP-1) 中响应 FLA 的促炎细胞因子“肿瘤坏死因子 α”(TNF-α) 的急性产生。总的来说，我们的研究结果表明，TLR5 介导的宿主和微生物群之间的串扰部分依赖于逆转录转座子的逆转录 (RT)。
Transposable elements (TEs) are mobile genomic sequences that encompass roughly 50% of the human genome. Class 1 TEs, or “retrotransposons,” mobilize through the production of an RNA intermediate that is then reverse transcribed to form complementary DNA (cDNA) molecules capable of genomic reinsertion. While TEs are traditionally silenced to maintain genomic integrity, the recognition of immunostimulatory cues, such as those provided by microorganisms, drastically alters host transcription to induce the differential expression of TEs. Emerging evidence demonstrates that the inducible production of TE cDNA is not an inert phenomenon but instead has been coopted by host immunity to facilitate cross talk between host and constituents of the microbiota by agonizing intrinsic antiviral receptors. Here, we demonstrate that immunostimulation of toll-like receptor 4 (TLR4) with lipopolysaccharide (LPS) and TLR5 with bacterial flagella (FLA) alters the expression of retrotransposons, such as human endogenous retroviruses (HERVs) and long interspersed nuclear elements (LINEs). Next, we demonstrate that reverse transcriptase inhibitor (RTi) delivery ameliorates the acute production of the proinflammatory cytokine “tumor necrosis factor alpha” (TNF-α) in response to FLA in a monocytic cell line (THP-1). Collectively, our findings demonstrate that TLR5-mediated cross talk between the host and microbiota is partially dependent on the reverse transcription (RT) of retrotransposons.
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影响因子：
64.5
作者：
Singh V;Yeoh BS;Chassaing B;Xiao X;Saha P;Aguilera Olvera R;Lapek JD Jr;Zhang L;Wang WB;Hao S;Flythe MD;Gonzalez DJ;Cani PD;Conejo-Garcia JR;Xiong N;Kennett MJ;Joe B;Patterson AD;Gewirtz AT;Vijay-Kumar M
通讯作者：
Vijay-Kumar M
影响因子：
3.3
作者：
Young GR;Mavrommatis B;Kassiotis G
通讯作者：
Kassiotis G
DOI：
10.1126/science.aad5497
发表时间：
2016-03-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chuong EB;Elde NC;Feschotte C
通讯作者：
Feschotte C
影响因子：
4.3
作者：
Bendall, Matthew L.;de Mulder, Miguel;Nixon, Douglas F.
通讯作者：
Nixon, Douglas F.
影响因子：
3.1
作者：
McDermott, PF;Ciacci-Woolwine, F;Mizel, SB
通讯作者：
Mizel, SB