ß-glucan triggers HSPCs mobilization by downregulating OSM in the bone marrow: a possible trained immunity strategy against sepsis in diabetes

β-glucan, a fungal cell wall polysaccharide, acts as an immunomodulator capable of inducing epigenetic and functional reprogramming in both terminally differentiated innate immune cells and hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM), a process known as trained immunity. Systemic β-glucan administration leads to HSPCs expansion, promotes myeloid-biased progenitor differentiation and enhances granulopoiesis. This β-glucan-induced trained immunity has been shown to confer protection against several types of cancers, as well as from infections such as Mycobacterium tuberculosis. Diabetes mellitus is a chronic metabolic disease characterizes by multiple BM microenvironmental defects, which impair HSPCs mobilization from the BM into peripheral blood (PB) in response to mobilizing stimuli (e.g., G-CSF or ischemia), a phenomenon known as “diabetic stem cell mobilopathy”. The reduction in circulating HSPCs, driven by the overexpression of Oncostatin M (OSM) in BM macrophages, contributes to an increased risk of future multi-organ damage and cardiovascular complications. Moreover, diabetic patients exhibit increased susceptibility to infections and septic complications, and markedly higher mortality. Although glucose control can partially rescue HSPCs mobilization, many patients fail to achieve adequate glucose targets. Increasing circulating HSPCs levels therefore represents a promising approach to modify the long-term risk of diabetic complications and improve patient outcomes. In this context, we investigated the effect of systemic β-glucan administration in diabetic and non-diabetic mice. We found that β-glucan induced a significant expansion of HSPCs in the BM, followed by a robust mobilization into the PB, both in diabetic and non-diabetic mice. This effect was associated with the downregulation of OSM levels in the BM, and with the suppression of BM-macrophages in diabetic mice. Importantly, Osm−/− mice failed to respond to β-glucan administration, demonstrating the requirement of OSM in this process. We further examined whether β-glucan confer protection against septic complications in diabetes, by remodeling the BM microenvironment. By employing an LPS-induced sepsis model, we showed that β-glucan pre-treatment restored the circulating HSPCs levels to baseline, preventing the decrease induced by LPS. Together, these findings suggest that β-glucan can restore defective HSPCs trafficking in diabetes by regulating OSM in the BM, both at steady state and under acute endotoxemia, and that β-glucan could represent a strategy to enhance sepsis resilience in diabetic subjects.