Zhu Enbo, Hu Lina, Wu Hongxian, Piao Limei, Zhao Guangxian, Inoue Aiko, Kim Weon, Yu Chenglin, Xu Wenhu, Bando Yasuko K, Li Xiang, Lei Yanna, Hao Chang-Ning, Takeshita Kyosuke, Kim Woo-Shik, Okumura Kenji, Murohara Toyoaki, Kuzuya Masafumi, Cheng Xian Wu
Department of Cardiology and ICU, Yanbian University Hospital, Yanji, China.
Department of and Community Healthcare & Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
J Am Heart Assoc. 2017 Jul 14;6(7):e006394. doi: 10.1161/JAHA.117.006394.
DPP4 (Dipeptidyl peptidase-4)-GLP-1 (glucagon-like peptide-1) and its receptor (GLP-1R) axis has been involved in several intracellular signaling pathways. The Adrβ3 (β3-adrenergic receptor)/CXCL12 (C-X-C motif chemokine 12) signal was required for the hematopoiesis. We investigated the novel molecular requirements between DPP4-GLP-1/GLP-1 and Adrβ3/CXCL12 signals in bone marrow (BM) hematopoietic stem cell (HSC) activation in response to chronic stress.
Male 8-week-old mice were subjected to 4-week intermittent restrain stress and orally treated with vehicle or the DPP4 inhibitor anagliptin (30 mg/kg per day). Control mice were left undisturbed. The stress increased the blood and brain DPP4 levels, the plasma epinephrine and norepinephrine levels, and the BM niche cell Adrβ3 expression, and it decreased the plasma GLP-1 levels and the brain GLP-1R and BM CXCL12 expressions. These changes were reversed by DPP4 inhibition. The stress activated BM sca-1c-KitCD48CD150 HSC proliferation, giving rise to high levels of blood leukocytes and monocytes. The stress-activated HSC proliferation was reversed by DPP4 depletion and by GLP-1R activation. Finally, the selective pharmacological blocking of Adrβ3 mitigated HSC activation, accompanied by an improvement of CXCL12 gene expression in BM niche cells in response to chronic stress.
These findings suggest that DPP4 can regulate chronic stress-induced BM HSC activation and inflammatory cell production via an Adrβ3/CXCL12-dependent mechanism that is mediated by the GLP-1/GLP-1R axis, suggesting that the DPP4 inhibition or the GLP-1R stimulation may have applications for treating inflammatory diseases.
二肽基肽酶4（DPP4）-胰高血糖素样肽1（GLP-1）及其受体（GLP-1R）轴参与了多种细胞内信号通路。肾上腺素能β3受体（Adrβ3）/CXC趋化因子配体12（CXCL12）信号对于造血作用是必需的。我们研究了在慢性应激反应中，DPP4-GLP-1/GLP-1与Adrβ3/CXCL12信号之间在骨髓（BM）造血干细胞（HSC）激活方面的新分子需求。
8周龄雄性小鼠接受4周的间歇性束缚应激，并口服给予溶媒或DPP4抑制剂阿格列汀（每天30毫克/千克）。对照小鼠不做处理。应激增加了血液和脑内的DPP4水平、血浆肾上腺素和去甲肾上腺素水平以及骨髓龛细胞Adrβ3的表达，同时降低了血浆GLP-1水平、脑内GLP-1R和骨髓CXCL12的表达。这些变化通过DPP4抑制得以逆转。应激激活了骨髓干细胞抗原-1（Sca-1）⁺c-Kit⁺CD48⁻CD150⁺造血干细胞的增殖，导致血液中白细胞和单核细胞水平升高。应激激活的造血干细胞增殖通过DPP4缺失和GLP-1R激活得以逆转。最后，Adrβ3的选择性药理学阻断减轻了造血干细胞的激活，同时伴随着骨髓龛细胞中CXCL12基因表达在慢性应激反应中的改善。
这些发现表明，DPP4可通过由GLP-1/GLP-1R轴介导的Adrβ3/CXCL12依赖性机制调节慢性应激诱导的骨髓造血干细胞激活和炎性细胞产生，提示DPP4抑制或GLP-1R刺激可能在治疗炎性疾病方面具有应用价值。
