Liraglutide attenuates high glucose-induced 'trained immunity' in cd34+ hematopoietic stem cells

Abstract Background Diabetes mellitus (DM) promotes aberrant immune cell activation, contributing to chronic inflammation and atherosclerosis. This process, known as "trained immunity", originates in hematopoietic stem cells (HSCs). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated immunomodulatory effects. Our recent findings showed that liraglutide (LIRA) prevents high glucose (HG)-induced oxidative stress and functional impairment of HSCs via GLP-1R activation. Here, we hypothesize that LIRA also mitigates HG-induced senescence and pro-inflammatory myeloid differentiation drift of HSCs. Purpose To evaluate the effects of LIRA on HG-induced senescence and myeloid differentiation of HSCs. Methods CD34+ HSCs from cord blood of healthy donors were expanded under normal-glucose (NG; 30 mM mannitol for osmotic control) or high-glucose (HG; 30 mM) conditions, with or without LIRA (100nM), in serum-free medium supplemented with FLT-3, SCF, IL-3, and IL-6 for up to 20 days. Gene expression of p21, p27, IL-6, TNFα, and NFkB-p65 was assessed by qPCR. ROS production and CD34+ HSC-derived monocyte subsets were analysed via flow cytometry, while cytokine secretion following lipopolysaccharide (LPS) stimulation was measured by ELISA. Results LIRA treatment significantly prevented HG-induced CD34+ HSCs proliferation impairment and the upregulation of senescence-associated secretory phenotype (SASP) genes, namely p21, p27, NFkB-p65, IL-6, and TNFα (one-way ANOVA; p≤0.05). These effects correlated with a marked reduction in HG-induced ROS production. Myeloid differentiation of HG-CD34+ HSCs resulted in the generation of monocytes mainly composed of an inflammatory and highly reactive intermediate monocyte subpopulation (CD14+CD16+), which exhibited increased LPS-induced IL-6 and TNFα secretion. LIRA treatment attenuated both the expansion of this inflammatory subpopulation (HG vs. HG-LIRA100, one-way ANOVA; p=0.054) and its pro-inflammatory phenotype. Conclusions Our data demostrate that immunomodulatory properites of GLP-1R agonist could be further explored for the treatment of immune system dysregulation in diabates.