Neuroimmunological communication via CGRP promotes the development of a regulatory phenotype in TLR4-stimulated macrophages
Neuroimmunological communication via CGRP promotes the development of a regulatory phenotype in TLR4-stimulated macrophages
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DOI：
10.1002/eji.201444553
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发表时间：
2014-12-01
影响因子：
5.4
通讯作者：
Holzmann, Bernhard
中科院分区：
文献类型：
--
作者：
Baliu-Pique, Mariona;Jusek, Gabriela;Holzmann, Bernhard
环境信号塑造了活化巨噬细胞的表型和功能。在这里，我们发现从感觉神经释放的神经肽降钙素基因相关肽（CGRP）通过增强调节巨噬细胞标记物IL-10、鞘氨酸激酶1 （SPHK1）和LIGHT（淋巴毒素样，表现出诱导表达，并与HSV糖蛋白D竞争疱疹病毒进入介质，一种由T淋巴细胞表达的受体）的表达来调节tlr4激活的小鼠巨噬细胞的表型。相比之下，CGRP抑制炎性巨噬细胞特征细胞因子的产生，并且不影响TLR4参与后伤口愈合巨噬细胞标志物的表达。在il -4刺激的巨噬细胞中，CGRP增加了LIGHT的表达，但不能诱导IL-10和SPHK1。CGRP对IL-10产生的刺激作用需要激活蛋白激酶A，并与CREB的延长磷酸化和CRTC2和CRTC3的持续核积累有关（其中CRTC是CREB调节的转录辅助因子）。CGRP在lps刺激的早期而非晚期增强了调节性巨噬细胞标志物的表达，这种作用与自分泌i型IFN活性无关。相比之下，自分泌i型IFN活性和IFN- β处理巨噬细胞促进了晚期IL-10的产生，但对LIGHT和SPHK1表达的影响很小。综上所述，这些结果确定了通过CGRP进行的神经免疫通讯是一种新的共刺激途径，促进了tlr4刺激的巨噬细胞调节表型的发展。CGRP似乎通过持续激活creb依赖性基因转录的机制起作用。
Environmental signals shape the phenotype and function of activated macrophages. Here, we show that the neuropeptide calcitonin gene-related peptide (CGRP), which is released from sensory nerves, modulates the phenotype of TLR4-activated murine macrophages by enhancing expression of the regulatory macrophage markers IL-10, sphingosine kinase 1 (SPHK1), and LIGHT (lymphotoxin-like, exhibits inducible expression and competes with HSV glycoprotein D for herpesvirus entry mediator, a receptor expressed by T lymphocytes). In contrast, CGRP inhibits production of cytokines characteristic of inflammatory macrophages and does not affect expression of wound-healing macrophage markers upon TLR4 engagement. In IL-4-stimulated macrophages, CGRP increased LIGHT expression, but failed to induce IL-10 and SPHK1. The stimulatory effect of CGRP on IL-10 production required activation of protein kinase A and was linked to prolonged phosphorylation of CREB and sustained nuclear accumulation of CRTC2 and CRTC3 (where CRTC is CREB-regulated transcriptional cofactor). CGRP enhanced expression of regulatory macrophage markers during the early, but not late, phase of LPS-stimulation and this effect was independent of autocrine type-I IFN activity. In contrast, autocrine type-I IFN activity and treatment of macrophages with IFN-beta promoted late-phase IL-10 production, but had only minor influence on LIGHT and SPHK1 expression. Together, the results identify neuroimmunological communication through CGRP as a novel costimulatory pathway promoting the development of a regulatory phenotype of TLR4-stimulated macrophages. CGRP appears to act through a mechanism that involves sustained activation of CREB-dependent gene transcription.