LRH-1 mitigates intestinal inflammatory disease by maintaining epithelial homeostasis and cell survival.
LRH-1 mitigates intestinal inflammatory disease by maintaining epithelial homeostasis and cell survival.
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DOI：
10.1038/s41467-018-06137-w
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发表时间：
2018-10-10
影响因子：
16.6
通讯作者：
Ingraham HA
中科院分区：
文献类型：
--
作者：
Bayrer JR;Wang H;Nattiv R;Suzawa M;Escusa HS;Fletterick RJ;Klein OD;Moore DD;Ingraham HA
上皮功能障碍和隐窝破坏是炎症性肠病（IBD）的定义特征。然而，目前缺乏靶向上皮功能障碍的IBD疗法。核受体LRH-1（NR 5A 2）在肠上皮中表达，并被认为有助于上皮更新。在这里，我们表明LRH-1维持肠上皮健康，并防止炎症损伤。敲除小鼠肠类器官中的LRH-1减少Notch信号传导，增加隐窝细胞死亡，扭曲上皮的细胞组成，并削弱上皮屏障。人LRH-1（hLRH-1）拯救上皮完整性，并且当过表达时，减轻鼠和人肠道类器官（包括源自IBD患者的那些）中的炎性损伤。最后，hLRH-1大大降低了T细胞介导的小鼠结肠炎的疾病严重程度。结合配体缺陷型hLRH-1突变体对TNFα损伤的保护作用的失败，这些发现提供了令人信服的证据，表明hLRH-1介导上皮稳态，是肠道疾病的一个有吸引力的靶点。炎症性肠病的特征在于上皮功能障碍。在这里，作者表明，核受体LRH-1的丢失通过改变小鼠肠道类器官中的Notch信号传导导致上皮破坏，并且LRH-1过表达改善了小鼠模型中的免疫介导的结肠炎。
Epithelial dysfunction and crypt destruction are defining features of inflammatory bowel disease (IBD). However, current IBD therapies targeting epithelial dysfunction are lacking. The nuclear receptor LRH-1 (NR5A2) is expressed in intestinal epithelium and thought to contribute to epithelial renewal. Here we show that LRH-1 maintains intestinal epithelial health and protects against inflammatory damage. Knocking out LRH-1 in murine intestinal organoids reduces Notch signaling, increases crypt cell death, distorts the cellular composition of the epithelium, and weakens the epithelial barrier. Human LRH-1 (hLRH-1) rescues epithelial integrity and when overexpressed, mitigates inflammatory damage in murine and human intestinal organoids, including those derived from IBD patients. Finally, hLRH-1 greatly reduces disease severity in T-cell-mediated murine colitis. Together with the failure of a ligand-incompetent hLRH-1 mutant to protect against TNFα-damage, these findings provide compelling evidence that hLRH-1 mediates epithelial homeostasis and is an attractive target for intestinal disease. Inflammatory bowel disease is characterised by epithelial dysfunction. Here the authors show that loss of the nuclear receptor LRH-1 leads to epithelial disruption by altering Notch signaling in mouse intestinal organoids, and that LRH-1 overexpression ameliorates immune-mediated colitis in a mouse model.
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影响因子：
64.8
作者：
Kernbauer, Elisabeth;Ding, Yi;Cadwell, Ken
通讯作者：
Cadwell, Ken
影响因子：
16
作者：
Sablin, EP;Krylova, IN;Ingraham, HA
通讯作者：
Ingraham, HA
影响因子：
16.8
作者：
Musille, Paul M.;Pathak, Manish C.;Lauer, Janelle L.;Hudson, William H.;Griffin, Patrick R.;Ortlund, Eric A.
通讯作者：
Ortlund, Eric A.
影响因子：
30.8
作者：
Barrett, Jeffrey C.;Lee, James C.;Lees, Charles W.;Prescott, Natalie J.;Anderson, Carl A.;Phillips, Anne;Wesley, Emma;Parnell, Kirstie;Zhang, Hu;Drummond, Hazel;Nimmo, Elaine R.;Massey, Dunecan;Blaszczyk, Kasia;Elliott, Timothy;Cotterill, Lynn;Dallal, Helen;Lobo, Alan J.;Mowat, Craig;Sanderson, Jeremy D.;Jewell, Derek P.;Newman, William G.;Edwards, Cathryn;Ahmad, Tariq;Mansfield, John C.;Satsangi, Jack;Parkes, Miles;Mathew, Christopher G.;Donnelly, Peter;Peltonen, Leena;Blackwell, Jenefer M.;Bramon, Elvira;Brown, Matthew A.;Casas, Juan P.;Corvin, Aiden;Craddock, Nicholas;Deloukas, Panos;Duncanson, Audrey;Jankowski, Janusz;Markus, Hugh S.;McCarthy, Mark I.;Palmer, Colin N. A.;Plomin, Robert;Rautanen, Anna;Sawcer, Stephen J.;Samani, Nilesh;Trembath, Richard C.;Viswanathan, Ananth C.;Wood, Nicholas;Spencer, Chris C. A.;Bellenguez, Celine;Davison, Daniel;Freeman, Colin;Strange, Amy;Langford, Cordelia;Hunt, Sarah E.;Edkins, Sarah;Gwilliam, Rhian;Blackburn, Hannah;Bumpstead, Suzannah J.;Dronov, Serge;Gillman, Matthew;Gray, Emma;Hammond, Naomi;Jayakumar, Alagurevathi;McCann, Owen T.;Liddle, Jennifer;Perez, Marc L.;Potter, Simon C.;Ravindrarajah, Radhi;Ricketts, Michelle;Waller, Matthew;Weston, Paul;Widaa, Sara;Whittaker, Pamela;Attwood, Antony P.;Stephens, Jonathan;Sambrook, Jennifer;Ouwehand, Willem H.;McArdle, Wendy L.;Ring, Susan M.;Strachan, David P.
通讯作者：
Strachan, David P.
影响因子：
3.7
作者：
de Jesus Cortez F;Suzawa M;Irvy S;Bruning JM;Sablin E;Jacobson MP;Fletterick RJ;Ingraham HA;England PM
通讯作者：
England PM