Kidney tissue hypoxia dictates T cell-mediated injury in murine lupus nephritis.
Kidney tissue hypoxia dictates T cell-mediated injury in murine lupus nephritis.
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DOI：
10.1126/scitranslmed.aay1620
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发表时间：
2020-04-08
影响因子：
17.1
通讯作者：
Craft J
中科院分区：
文献类型：
--
作者：
Chen PM;Wilson PC;Shyer JA;Veselits M;Steach HR;Cui C;Moeckel G;Clark MR;Craft J
肾脏经常是自身免疫损伤的目标，包括系统性红斑狼疮；然而，免疫细胞如何适应肾脏独特的环境并导致组织损伤尚不清楚。我们发现，在狼疮性肾炎中，正常情况下氧分压较低的肾组织会变得更加缺氧。在损伤的小鼠组织中，肾脏浸润的CD4+和CD8+T细胞表达低氧诱导因子-1(HIF-1)，改变了它们的细胞代谢，防止了它们在低氧条件下的凋亡。在人类狼疮性肾炎中，HIF-1依赖的基因调控通路也上调了肾脏浸润性T细胞。选择性HIF-1阻断对这些环境适应的干扰抑制了T细胞的渗透，并逆转了狼疮小鼠模型的组织缺氧和损伤。提示靶向HIF-1治疗自身免疫性疾病的肾损伤可能是有效的。在小鼠模型中，HIF-1决定了T细胞在狼疮中渗透的效应功能，导致的组织损伤可以通过阻断HIF-1来消除。
The kidney is a frequent target of autoimmune injury, including in systemic lupus erythematosus; however, how immune cells adapt to kidney’s unique environment and contribute to tissue damage is unknown. We found that renal tissue, which normally has low oxygen tension, becomes more hypoxic in lupus nephritis. In the injured mouse tissue, renal-infiltrating CD4+ and CD8+ T cells express hypoxia-inducible factor-1 (HIF-1), which alters their cellular metabolism and prevents their apoptosis in hypoxia. HIF-1-dependent gene-regulated pathways were also upregulated renal-infiltrating T cells in human lupus nephritis. Perturbation of these environmental adaptations by selective HIF-1 blockade inhibited infiltrating T cells and reversed tissue hypoxia and injury in murine models of lupus. The results suggest that targeting HIF-1 might be effective for treating renal injury in autoimmune diseases. HIF-1 dictates effector function of infiltrating T cells in lupus, causing tissue damage that can be abrogated by its blockade in murine models.
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DOI：
10.1083/jcb.201504047
发表时间：
2015-09-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Gang H;Dhingra R;Lin J;Hai Y;Aviv Y;Margulets V;Hamedani M;Thanasupawat T;Leygue E;Klonisch T;Davie JR;Kirshenbaum LA
通讯作者：
Kirshenbaum LA
影响因子：
14.9
作者：
Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
通讯作者：
Ma'ayan A
影响因子：
64.8
作者：
Jiang L;Shestov AA;Swain P;Yang C;Parker SJ;Wang QA;Terada LS;Adams ND;McCabe MT;Pietrak B;Schmidt S;Metallo CM;Dranka BP;Schwartz B;DeBerardinis RJ
通讯作者：
DeBerardinis RJ
影响因子：
64.8
作者：
Cho, Sung Hoon;Raybuck, Ariel L.;Stengel, Kristy;Wei, Mei;Beck, Thomas C.;Volanakis, Emmanuel;Thomas, James W.;Hiebert, Scott;Haase, Volker H.;Boothby, Mark R.
通讯作者：
Boothby, Mark R.
影响因子：
4.8
作者：
Gameiro, Paulo A.;Laviolette, Laura A.;Stephanopoulos, Gregory
通讯作者：
Stephanopoulos, Gregory