Toll-like receptor 8 ligands activate a vitamin D mediated autophagic response that inhibits human immunodeficiency virus type 1.
Toll-like receptor 8 ligands activate a vitamin D mediated autophagic response that inhibits human immunodeficiency virus type 1.
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Toll样受体8配体激活维生素D介导的自噬反应，从而抑制人类免疫缺陷病毒1型。
DOI：
10.1371/journal.ppat.1003017
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Spector SA
中科院分区：
文献类型：
--
作者：
Campbell GR;Spector SA
Toll样受体（TLR）在识别微生物病原体和触发宿主先天性免疫应答（包括自噬）以及在人类免疫缺陷病毒1型（HIV）感染期间介导免疫激活方面是重要的。我们在此报告，TLR 8在人巨噬细胞中的激活诱导人凯萨林菌素微生物肽（CAMP）、维生素D受体（VDR）和细胞色素P450家族27亚家族B多肽1（CYP 27 B1）的表达，该多肽1α-羟基化维生素D的非活性形式25-羟基胆钙化醇，使其成为具有生物活性的代谢产物。此外，我们证明使用RNA干扰，化学抑制剂和维生素D缺乏的介质，TLR 8激动剂通过维生素D和CAMP依赖性自噬机制抑制HIV。这些数据支持维生素D在控制HIV感染方面的重要作用，并为维生素D的益处提供了生物学解释。这些发现还为预防和治疗HIV感染的潜在新靶点提供了新的见解。细胞使用大自噬（自噬-响应于应激的细胞内组分的“自食”、溶酶体依赖性降解和再循环）作为通过模式识别受体（例如Toll样受体（TLR））检测细胞内病原体的机制，所述模式识别受体识别病原体的对其生存至关重要的特征分子。一种这样的Toll样受体TLR 8位于人巨噬细胞内体中，识别咪唑并喹啉化合物和富含尿苷的单链RNA，例如人免疫缺陷病毒1型（HIV）单链RNA。在本研究中，我们报告了TLR 8在人巨噬细胞中的激活诱导人凯萨林菌素微生物肽（CAMP）、维生素D受体（VDR）和细胞色素P450家族27亚家族B多肽1（CYP 27 B1）的表达，该多肽1α-羟基化维生素D的非活性形式25-羟基胆钙化醇，使其成为具有生物活性的代谢产物。此外，我们证明TLR 8激活通过维生素D和cAMP依赖性机制诱导人巨噬细胞自噬，并且TLR 8激动剂诱导自噬抑制HIV。这些数据支持维生素D在控制HIV感染方面的重要作用，并为维生素D的益处提供了生物学解释。这些发现还为预防和治疗HIV感染的潜在新靶点提供了新的见解。
Toll-like receptors (TLR) are important in recognizing microbial pathogens and triggering host innate immune responses, including autophagy, and in the mediation of immune activation during human immunodeficiency virus type-1 (HIV) infection. We report here that TLR8 activation in human macrophages induces the expression of the human cathelicidin microbial peptide (CAMP), the vitamin D receptor (VDR) and cytochrome P450, family 27, subfamily B, polypeptide 1 (CYP27B1), which 1α-hydroxylates the inactive form of vitamin D, 25-hydroxycholecalciferol, into its biologically active metabolite. Moreover, we demonstrate using RNA interference, chemical inhibitors and vitamin D deficient media that TLR8 agonists inhibit HIV through a vitamin D and CAMP dependent autophagic mechanism. These data support an important role for vitamin D in the control of HIV infection, and provide a biological explanation for the benefits of vitamin D. These findings also provide new insights into potential novel targets to prevent and treat HIV infection. Cells use macroautophagy (autophagy - ‘self-eating’, lysosome-dependent degradation and recycling of intracellular components in response to stress) as a mechanism to detect intracellular pathogens through pattern-recognition receptors such as Toll-like receptors (TLRs) that recognize signature molecules of pathogens that are essential for their survival. One such Toll-like receptor, TLR8, which is located in human macrophage endosomes, recognizes both imidazoquinoline compounds and uridine-rich single-stranded RNA such as human immunodeficiency virus type-1 (HIV) single-stranded RNA. In the present study we report that TLR8 activation in human macrophages induces the expression of the human cathelicidin microbial peptide (CAMP), the vitamin D receptor (VDR), and cytochrome P450, family 27, subfamily B, polypeptide 1 (CYP27B1), which 1α-hydroxylates the inactive form of vitamin D, 25-hydroxycholecalciferol, into its biologically active metabolite. Moreover, we demonstrate that TLR8 activation induces autophagy in human macrophages through a vitamin D and CAMP dependent mechanism, and that the induction of autophagy by TLR8 agonists inhibits HIV. These data support an important role for vitamin D in the control of HIV infection, and provide a biological explanation for the benefits of vitamin D. These findings also provide new insights into potential novel targets to prevent and treat HIV infection.
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DOI：
10.1083/jcb.200609050
发表时间：
2007-04-23
期刊：
The Journal of cell biology
影响因子：
--
作者：
Deneka M;Pelchen-Matthews A;Byland R;Ruiz-Mateos E;Marsh M
通讯作者：
Marsh M
影响因子：
6.7
作者：
Grégoire IP;Richetta C;Meyniel-Schicklin L;Borel S;Pradezynski F;Diaz O;Deloire A;Azocar O;Baguet J;Le Breton M;Mangeot PE;Navratil V;Joubert PE;Flacher M;Vidalain PO;André P;Lotteau V;Biard-Piechaczyk M;Rabourdin-Combe C;Faure M
通讯作者：
Faure M
p62/SQSTM1形成自噬降解的蛋白质聚集体，并对亨廷顿蛋白诱导的细胞死亡具有保护作用。
影响因子：
7.8
作者：
Bjorkoy, Geir;Lamark, Trond;Brech, Andreas;Outzen, Heidi;Perander, Maria;Overvatn, Aud;Stenmark, Harald;Johansen, Terje
通讯作者：
Johansen, Terje
影响因子：
32.4
作者：
Blanchet FP;Moris A;Nikolic DS;Lehmann M;Cardinaud S;Stalder R;Garcia E;Dinkins C;Leuba F;Wu L;Schwartz O;Deretic V;Piguet V
通讯作者：
Piguet V
影响因子：
6.7
作者：
Campbell GR;Spector SA
通讯作者：
Spector SA