DNA attenuates enterocyte Toll-like receptor 4-mediated intestinal mucosal injury after remote trauma.
DNA attenuates enterocyte Toll-like receptor 4-mediated intestinal mucosal injury after remote trauma.
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DOI：
10.1152/ajpgi.00373.2010
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发表时间：
2011-05
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影响因子：
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通讯作者：
C. Sodhi;Ryan M. Levy;Roop Gill;M. Neal;W. Richardson;M. Branca;A. Russo;T. Prindle;T. Billiar;D. Hackam
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文献类型：
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作者：
C. Sodhi;Ryan M. Levy;Roop Gill;M. Neal;W. Richardson;M. Branca;A. Russo;T. Prindle;T. Billiar;D. Hackam
肠粘膜损伤发生在远程创伤后，尽管感知远程损伤并导致肠上皮破坏的机制仍不完全清楚。我们现在假设，Toll样受体4（TLR4）信号传导对肠上皮细胞在远程损伤后，可能通过内源性TLR4配体高迁移率族蛋白1（HMGB1），可能会导致肠道功能障碍和细菌易位和TLR9与DNA的激活可以逆转这些影响。为了支持这一假设，TLR4表达小鼠暴露于双侧股骨骨折和全身性低血压导致TLR4表达和信号传导增加以及回肠粘膜破坏，导致细菌移位，这在TLR4突变小鼠中未观察到。这种效应需要肠上皮细胞而不是免疫细胞中的TLR4信号传导，因为腺病毒介导的肠上皮细胞中TLR4的抑制阻止了这些发现。在寻求确定内源性TLR4配体参与，HMGB1的表达增加，在野生型，但不是TLR4突变体，小鼠损伤后的肠粘膜，和管理的抗HMGB1抗体减少肠粘膜TLR4信号和细菌易位后远程创伤。引人注目的是，粘膜损伤显着增加TLR9突变小鼠，而外源性DNA的管理TLR4介导的肠上皮细胞凋亡的程度降低，恢复粘膜愈合，并保持组织完整性的肠屏障后远程损伤。总之，这些发现确定了远程损伤和肠细胞TLR4信号传导之间的新联系，可能通过HMGB1作为配体导致屏障损伤，并证明了通过激活TLR9逆转这些不良反应。
Intestinal mucosal injury occurs after remote trauma although the mechanisms that sense remote injury and lead to intestinal epithelial disruption remain incompletely understood. We now hypothesize that Toll-like receptor 4 (TLR4) signaling on enterocytes after remote injury, potentially through the endogenous TLR4 ligand high-mobility group box-1 (HMGB1), could lead to intestinal dysfunction and bacterial translocation and that activation of TLR9 with DNA could reverse these effects. In support of this hypothesis, exposure of TLR4-expressing mice to bilateral femur fracture and systemic hypotension resulted in increased TLR4 expression and signaling and disruption of the ileal mucosa, leading to bacterial translocation, which was not observed in TLR4-mutant mice. TLR4 signaling in enterocytes, not immune cells, was required for this effect, as adenoviral-mediated inhibition of TLR4 in enterocytes prevented these findings. In seeking to identify the endogenous TLR4 ligands involved, the expression of HMGB1 was increased in the intestinal mucosa after injury in wild-type, but not TLR4-mutant, mice, and administration of anti-HMGB1 antibodies reduced both intestinal mucosal TLR4 signaling and bacterial translocation after remote trauma. Strikingly, mucosal injury was significantly increased in TLR9-mutant mice, whereas administration of exogenous DNA reduced the extent of TLR4-mediated enterocyte apoptosis, restored mucosal healing, and maintained the histological integrity of the intestinal barrier after remote injury. Taken together, these findings identify a novel link between remote injury and enterocyte TLR4 signaling leading to barrier injury, potentially through HMGB1 as a ligand, and demonstrate the reversal of these adverse effects through activation of TLR9.