Activation of lipoxin A(4) receptors by aspirin-triggered lipoxins and select peptides evokes ligand-specific responses in inflammation.
Activation of lipoxin A(4) receptors by aspirin-triggered lipoxins and select peptides evokes ligand-specific responses in inflammation.
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DOI：
10.1084/jem.191.7.1197
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发表时间：
2000-04-03
影响因子：
15.3
通讯作者：
Serhan, C N
中科院分区：
文献类型：
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作者：
Chiang, N;Fierro, I M;Gronert, K;Serhan, C N
脂氧素 (LX) A4 和阿司匹林触发的 LX (ATL) 是内源性脂质，可通过特定的 LXA4 受体 (ALXR) 调节白细胞运输并介导抗炎和消退。 ATL 类似物可显着抑制人中性粒细胞（多形核白细胞 [PMN]）由源自线粒体的强效坏死肽以及流氓合成趋化肽引起的反应。这些生物活性脂质类似物和小肽各自选择性地与重组人 ALXR 竞争特定的 3H-LXA4 结合，并且其 N-糖基化被证明对于肽而非 LXA4 识别至关重要。由功能相反的受体，即 ALXR 和白三烯 B4 受体 (BLT) 构建的嵌合受体表明，ALXR 的第七跨膜片段和邻近区域对于 LXA4 识别至关重要，而 ALXR 的其他区域对于肽配体的高亲和力结合是必需的。总之，这些发现首次表明单个七次跨膜受体可以将某些趋化肽的识别和功能转变为对 ATL 和 LX（脂质配体）的抑制。此外，他们认为通过 LX 或 ATL 激活 ALXR 可以保护宿主免受与先天免疫相关的潜在有害的 PMN 反应，以及通过识别肽片段而产生的组织损伤中的直接效应反应。
Lipoxin (LX) A4 and aspirin-triggered LX (ATL) are endogenous lipids that regulate leukocyte trafficking via specific LXA4 receptors (ALXRs) and mediate antiinflammation and resolution. ATL analogues dramatically inhibited human neutrophil (polymorphonuclear leukocyte [PMN]) responses evoked by a potent necrotactic peptide derived from mitochondria as well as a rogue synthetic chemotactic peptide. These bioactive lipid analogues and small peptides each selectively competed for specific 3H-LXA4 binding with recombinant human ALXR, and its N-glycosylation proved essential for peptide but not LXA4 recognition. Chimeric receptors constructed from receptors with opposing functions, namely ALXR and leukotriene B4 receptors (BLTs), revealed that the seventh transmembrane segment and adjacent regions of ALXR are essential for LXA4 recognition, and additional regions of ALXR are required for high affinity binding of the peptide ligands. Together, these findings are the first to indicate that a single seven-transmembrane receptor can switch recognition as well as function with certain chemotactic peptides to inhibitory with ATL and LX (lipid ligands). Moreover, they suggest that ALXR activation by LX or ATL can protect the host from potentially deleterious PMN responses associated with innate immunity as well as direct effector responses in tissue injury by recognition of peptide fragments.