Adrenergic Signalling Drives Accumulation of Myeloid-derived Suppressor Cells in the Liver During Stress

Introduction/Rationale: Psychological stress, due to exposure to environmental and/or emotional stressors, has long been associated with immune dysfunction and immunosuppression. Previous studies have largely focused on the effects of chronic stress on conventional myeloid cells which have been shown to be afflicted by stress-induced apoptosis. However, how stress modulates immune responses elicited by unconventional myeloid cells remains poorly understood.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature-myeloid lineage cells with potent immunosuppressive properties, commonly enriched in the tumor microenvironment. Despite their well-established role in various malignancies, mechanisms governing their accumulation and activity in stress are largely unexplored.

Methods: In this study, we used a prolonged restraint model to investigate the effects of chronic stress on MDSCs in the bone marrow, blood, spleen and liver of C57BL/6 mice. Cells were analyzed using a combination of flow cytometry, qPCR and histological staining.

Results: Here, we demonstrate that prolonged restraint results in the accumulation of MDSCs selectively in the liver. Notably, these MDSCs unusually co-express high levels of Ly6C and Ly6G, deviating from conventional monocytic (Ly6ChiLy6G-) or granulocytic (Ly6CloLy6G+) MDSC phenotypes in mice. This influx of MDSCs appears to be mediated through IL-6 and G-CSF, as well as the stress-associated neurotransmitters, norepinephrine and epinephrine. Additionally, abrogation of signalling through the IL-6R, G-CSFR and/or adrenergic receptors are successful in preventing intrahepatic MDSC accumulation.

Conclusion: Our findings reveal a novel stress-mediated mechanism of MDSC expansion in the liver, which may contribute to the establishment of a pre-metastatic niche or a tumor-promoting microenvironment. Understanding neuroimmune crosstalk that drives MDSC accumulation provides critical insights into how psychological stress influences cancer progression and immune evasion.