Abstract
Background: Dipeptidyl peptidase-4 (DPP4) inhibition exhibits multiple pleotrophic effects. Hematopoietic stem cell (HSC) activation has been implicated in the pathogenesis of stress-related metabolic disorder and cardiovascular disease. Given that interaction between β3-adrenergic receptor (Adrβ3) signaling and the immune system may link stress and the initiation and progression of disorders, we investigated whether DPP4 regulates immune over-reactions in a chronic stress mouse model, focusing on HSC activation. Methods and Results: Male 8-week-old mice fed a normal diet underwent chronic stress were randomly assigned to one of three groups and administered vehicle or a low or high dose of the DPP4 inhibitor anagliptin. Control mice were left undisturbed. The stress increased the blood and brain DPP4 activity, the levels of plasma adrenaline and noradrenaline, and the bone marrow (BM) niche cell adrenergic receptor (Adrβ3) expression, and it decreased the levels of plasma glucagon-like peptide (GLP-1) as well as brain GLP-1 receptor (GLP-1R) and BM Cxcl12 expressions. These changes were reversed by DPP4 inhibition. The stress activated the BM sca-1 high c-Kit high CD48 low CD150 high HSC proliferation, giving rise to high levels of blood leukocytes and monocytes. These DPP4 inhibition-related benefits were mimicked by DPP4 depletion and by GLP-1R activation. Adrβ3 inhibition mitigated BM Cxcl12 expressions and HSC activation. Conclusions: DPP4 activity appears to regulate chronic stress-induced BM HSC activation and inflammatory cell production via an Adrβ3-CXCLl12-dependent mechanism that is mediated by the GLP-1-GLP-1R axis, suggesting that the inhibition of DPP4 or the stimulation of GLP-1R may have applications in the treatment of inflammatory diseases.
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