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血清素通过 5-HT7R-PKA 信号轴驱动致纤维化和抗炎基因谱的获得。

Serotonin drives the acquisition of a profibrotic and anti-inflammatory gene profile through the 5-HT7R-PKA signaling axis.

机构信息

Myeloid Cell Laboratory, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain.

Servicio de Reumatología, Instituto de Investigación Hospital 12 de octubre, Universidad Complutense de Madrid, Madrid, Spain.

出版信息

Sci Rep. 2017 Nov 7;7(1):14761. doi: 10.1038/s41598-017-15348-y.

DOI:10.1038/s41598-017-15348-y
PMID:29116249
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5676747/
Abstract

Peripheral serotonin (5-hydroxytryptamine, 5-HT) regulates cell growth and differentiation in numerous cell types through engagement of seven types of cell surface receptors (HTR1-7). Deregulated 5-HT/HTR levels contribute to pathology in chronic inflammatory diseases, with macrophages being relevant targets for the physio-pathological effects of 5-HT. In fact, 5-HT skews human macrophage polarization through engagement of 5-HT2BR and 5-HT7R receptors. We now report that 5-HT primes macrophages for reduced pro-inflammatory cytokine production and IFN type I-mediated signaling, and promotes an anti-inflammatory and pro-fibrotic gene signature in human macrophages. The acquisition of the 5-HT-dependent gene profile primarily depends on the 5-HT7R receptor and 5-HT7R-initiated PKA-dependent signaling. In line with the transcriptional results, 5-HT upregulates TGFβ1 production by human macrophages in an HTR7- and PKA-dependent manner, whereas the absence of Htr7 in vivo results in diminished macrophage infiltration and collagen deposition in a mouse model of skin fibrosis. Our results indicate that the anti-inflammatory and pro-fibrotic activity of 5-HT is primarily mediated through the 5-HT7R-PKA axis, and that 5-HT7R contributes to pathology in fibrotic diseases.

摘要

外周血清素（5-羟色胺，5-HT）通过与七种细胞表面受体（HTR1-7）结合，调节多种细胞类型的细胞生长和分化。5-HT/HTR 水平失调会导致慢性炎症性疾病的病理发生，巨噬细胞是 5-HT 生理病理作用的相关靶标。事实上，5-HT 通过与 5-HT2BR 和 5-HT7R 受体结合，使人类巨噬细胞发生极化。我们现在报告称，5-HT 使巨噬细胞能够减少促炎细胞因子的产生和 IFN 型 I 介导的信号转导，并促进人类巨噬细胞中抗炎和抗纤维化的基因特征。获得 5-HT 依赖性基因谱主要取决于 5-HT7R 受体和 5-HT7R 启动的 PKA 依赖性信号转导。与转录结果一致，5-HT 以 HTR7 和 PKA 依赖性方式上调人类巨噬细胞中 TGFβ1 的产生，而体内 Htr7 的缺失会导致皮肤纤维化小鼠模型中巨噬细胞浸润和胶原沉积减少。我们的研究结果表明，5-HT 的抗炎和抗纤维化活性主要是通过 5-HT7R-PKA 轴介导的，并且 5-HT7R 参与了纤维化疾病的病理发生。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fc/5676747/ef14b9bdfbf9/41598_2017_15348_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fc/5676747/a305a6dbc258/41598_2017_15348_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fc/5676747/d420751e6e8f/41598_2017_15348_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fc/5676747/9192a29265ff/41598_2017_15348_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fc/5676747/858633ef9cee/41598_2017_15348_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fc/5676747/23a5a05c8abd/41598_2017_15348_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fc/5676747/ef14b9bdfbf9/41598_2017_15348_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fc/5676747/a305a6dbc258/41598_2017_15348_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fc/5676747/d420751e6e8f/41598_2017_15348_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fc/5676747/9192a29265ff/41598_2017_15348_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fc/5676747/858633ef9cee/41598_2017_15348_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fc/5676747/23a5a05c8abd/41598_2017_15348_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21fc/5676747/ef14b9bdfbf9/41598_2017_15348_Fig6_HTML.jpg

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