CGRP-CRLR / RAMP1信号对于应激诱导的造血作用很重要。,Scientific Reports

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CGRP-CRLR / RAMP1信号对于应激诱导的造血作用很重要。
Scientific Reports ( IF 3.8 ) Pub Date : 2019-01-23 , DOI: 10.1038/s41598-018-36796-0
Akira Suekane ₁ , Yusuke Saito ₁ , Shingo Nakahata ₁ , Tomonaga Ichikawa ₁ , Honami Ogoh ₁ , Kazutake Tsujikawa ₂ , Kazuhiro Morishita ₁

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嗜生性病毒整合位点1（EVI1）在正常和恶性造血功能中起着至关重要的作用。由于我们先前在具有高EVI1表达的急性粒细胞白血病（AML）中确定了降钙素受体样受体（CRLR）的高表达，因此在此我们表征了CRLR在造血中的功能。由于在未成熟的造血骨髓（BM）细胞中发现了较高的CRLR表达和受体活性修饰蛋白1（RAMP1），因此我们着重于降钙素基因相关肽（CGRP），它是CRLR / RAMP1复合物的特异性配体。为了阐明CGRP在造血中的作用，使用了Ramp1缺陷型（Ramp1-/-）小鼠。Ramp1-/-小鼠几乎维持稳态血细胞生成。但是，Ramp1-/-小鼠的BM繁殖能力显着降低，移植的Ramp1-/-BM单核细胞增殖能力低，活性氧（ROS）产生和细胞凋亡增加。因此，CGRP对于在增殖性应激的短暂暴露过程中维持造血功能很重要。此外，连续CGRP暴露于小鼠两周可诱导BM未成熟造血细胞和分化的髓样细胞数量减少。由于已知CGRP在炎症条件下增加以调节免疫反应，因此在慢性炎症条件下持续CGRP分泌引起的造血衰竭可能是抗炎症反应的重要机制之一。CGRP对于暂时性增生应激暴露期间维持造血功能很重要。此外，连续CGRP暴露于小鼠两周可诱导BM未成熟造血细胞和分化的髓样细胞数量减少。由于已知CGRP在炎症条件下增加以调节免疫反应，因此在慢性炎症条件下持续CGRP分泌引起的造血衰竭可能是抗炎症反应的重要机制之一。CGRP对于暂时性增生应激暴露期间维持造血功能很重要。此外，连续CGRP暴露于小鼠两周可诱导BM未成熟造血细胞和分化的髓样细胞数量减少。由于已知CGRP在炎症条件下增加以调节免疫反应，因此在慢性炎症条件下持续CGRP分泌引起的造血衰竭可能是抗炎症反应的重要机制之一。

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CGRP-CRLR/RAMP1 signal is important for stress-induced hematopoiesis.

Ecotropic viral integration site-1 (EVI1) has a critical role in normal and malignant hematopoiesis. Since we previously identified high expression of calcitonin receptor like receptor (CRLR) in acute myeloid leukemia (AML) with high EVI1 expression, we here characterized the function of CRLR in hematopoiesis. Since higher expression of CRLR and receptor activity modifying protein 1 (RAMP1) was identified in immature hematopoietic bone marrow (BM) cells, we focused on calcitonin gene-related peptide (CGRP), a specific ligand for the CRLR/RAMP1 complex. To elucidate the role of CGRP in hematopoiesis, Ramp1-deficient (Ramp1−/−) mice were used. The steady-state hematopoiesis was almost maintained in Ramp1−/− mice; however, the BM repopulation capacity of Ramp1−/− mice was significantly decreased, and the transplanted Ramp1−/− BM mononuclear cells had low proliferation capacity with enhanced reactive oxygen species (ROS) production and cell apoptosis. Thus, CGRP is important for maintaining hematopoiesis during temporal exposures with proliferative stress. Moreover, continuous CGRP exposure to mice for two weeks induced a reduction in the number of BM immature hematopoietic cells along with differentiated myeloid cells. Since CGRP is known to be increased under inflammatory conditions to regulate immune responses, hematopoietic exhaustion by continuous CGRP secretion under chronic inflammatory conditions is probably one of the important mechanisms of anti-inflammatory responses.

更新日期：2019-01-23

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