Tissue damage negatively regulates LPS-induced macrophage necroptosis
Tissue damage negatively regulates LPS-induced macrophage necroptosis
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DOI：
10.1038/cdd.2016.21
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发表时间：
2016-09-01
影响因子：
12.4
通讯作者：
Fan, J.
中科院分区：
文献类型：
--
作者：
Li, Z.;Scott, M. J.;Fan, J.
感染是外科手术和严重创伤后组织损伤的常见临床并发症。研究表明，由先前的创伤/组织损伤引起的细胞预激活会深刻影响先天免疫细胞对继发性感染刺激的反应。细胞坏死坏死是一种受调节的炎症细胞死亡形式，是控制细胞从巨噬细胞（M.）等重要先天免疫执行细胞释放炎症介质的机制之一，巨噬细胞对炎症的进展起着关键的调节作用。在这项研究中，我们利用模拟长骨骨折的小鼠模型，研究了创伤/组织损伤在lps诱导的坏死性上睑下垂中的调节机制和作用。我们证明LPS通过toll样受体（TLR） 4促进M. necroptosis。然而，坏死上睑下垂可通过从受损组织中释放高迁移率组盒1 （HMGB1）而得到改善。我们发现HMGB1通过晚期糖基化终产物细胞表面受体（RAGE）上调小窝蛋白-1的表达，进而诱导小窝介导的TLR4内化和脱敏，从而减少M.坏死性坏死。我们进一步表明，RAGE-MyD88激活Cdc42和随后的转录因子Sp1激活是小窝蛋白-1转录上调的机制。这些结果揭示了损伤相关分子模式（DAMP）分子在对外源性病原体相关分子模式分子的反应中限制炎症的保护作用。
Infection is a common clinical complication following tissue damage resulting from surgery and severe trauma. Studies have suggested that cell pre-activation by antecedent trauma/tissue damage profoundly impacts the response of innate immune cells to a secondary infectious stimulus. Cell necroptosis, a form of regulated inflammatory cell death, is one of the mechanisms that control cell release of inflammatory mediators from important innate immune executive cells such as macrophages (M.), which critically regulate the progress of inflammation. In this study, we investigated the mechanism and role of trauma/tissue damage in the regulation of LPS-induced M. necroptosis using a mouse model simulating long-bone fracture. We demonstrate that LPS acting through Toll-like receptor (TLR) 4 promotes M. necroptosis. However, necroptosis is ameliorated by high-mobility group box 1 (HMGB1) release from damaged tissue. We show that HMGB1 acting through cell surface receptor for advanced glycation end products (RAGE) upregulates caveolin-1 expression, which in turn induces caveolae-mediated TLR4 internalization and desensitization to decrease M. necroptosis. We further show that RAGE-MyD88 activation of Cdc42 and subsequent activation of transcription factor Sp1 serves as a mechanism underlying caveolin-1 transcriptional upregulation. These results reveal a previous unidentified protective role of damage-associated molecular pattern (DAMP) molecules in restricting inflammation in response to exogenous pathogen-associated molecular pattern molecules.