Accumulation of Myeloid-Derived Suppressor Cells – Immunosuppression
Jianfeng Jin et al. identify a possible new mechanism mediating immunosuppression following chronic stress. These findings are published in the September 2013 issue of PLoS One.
Stress is defined as a state of threatened homeostasis. The principal stress hormones glucocorticoids and catecholamines affect major immune functions such as antigen presentation, NK cells functions, leukocyte proliferation and traffic, secretion of cytokines and antibodies, and selection of the T helper (Th) 1 versus Th2 and Th17 responses.
Stress has been regarded as immunosuppressive but recent evidence indicates that stress hormones influence the immune response in a less monochromatic way – systemically they inhibit Th1/pro-inflammatory responses and induce a Th2 shift. Thus, systemically stress might suppress cellular immunity but boost humoral immunity. But acute stress might induce pro-inflammatory activities in certain tissues through neural activation of the peripheral corticotropin-releasing hormone-mast cell-histamine axis and other mechanisms.
Yet, the role of stress in the regulation of the newly identified immature myeloid cells – the myeloid-derived suppressor cells (MDSCs) is much less understood.
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that are characterized by the ability to suppress both innate and adaptive immune responses. They suppress immune responses and expand during cancer, infection, and inflammatory disease. In fact, these cells – first reported around 30 years ago – represent pathologically activated neutrophils and monocytes with potent immunosuppressive activity. Yet, recent evidence indicates key distinctions between MDSCs and classical neutrophils and monocytes.
It is known that in tumor microenvironments, MDSC expansion is stimulated by prostaglandin E2 (PGE2) and vascular endothelial growth factor (VEGF). Hence, the authors of the PLoS One study hypothesized that there may be a relationship between prolonged psychological stress and MDSCs.
The investigators report that chronic psychological stress led to the accumulation of CD11b+Gr1+ cells in the bone marrow of BALB/c mice. A mouse model using restraint as a chronic stressor was utilized, and bone marrow, spleen, and thymus were examined.
The authors found that chronic psychological stress induced a significantly higher percentage of CD11b+Gr1+ cells in the bone marrow and an increase in the absolute number of CD11b+Gr1+ cells in this organ. Similar accumulation of CD11b+Gr1+ cells was also seen in the peripheral blood of stressed mice.
PGE2 levels but not VEGF levels were found to be elevated, and catecholamines also appeared to play a role in MDSC accumulation, as β-adrenergic receptor blockade with propranolol partially reversed the noted accumulation.
Of note, blocking the effects of glucocorticoids by the co-administration of RU486 and antalarmin showed no effect on the increased percentage of bone marrow CD11b+Gr1+ cells under the condition of chronic psychological stress. On the other side, β-adrenergic blockade with propranolol inhibited, to an extent the MDSC accumulation.
However, daily injection with epinephrine or isoproterenol for five consecutive days had no effect on the percentage of CD11b+Gr1+ cells in the bone marrow. Taken together, the data indicate that catecholamines collaborated with other factors to induce the accumulation of CD11b+Gr1+ cells.
Thus, the COX-2 specific inhibitor SC-236 reversed the increased percentage of this population. As the biosynthetic pathway for PGE2 depends on the inducible cyclooxygenase 2 (COX-2) enzyme and catecholamines contribute to COX-2 induction under a pro-inflammatory environment, the authors suggest that the COX-2-PGE2 loop mediates the MDSCs accumulation downstream of catecholamines. COX-2-PGE2 loop might collaborate with other factors to induce MDSCs accumulation via promoting expansion, conversion, better persistence, and/or mobilization.
Of note, bone marrow CD11b+Gr1+ cells isolated from stressed mice produced more TNF-α upon LPS stimulation, but exhibited higher ability to induce the production of IL-10 in primary macrophages. The authors conclude that all these results suggest that MDSCs contribute to chronic psychological stress-induced immunosuppression through an increase in the number and a shift to their phenotype and function.
This study highlights the complex interplay between psychological stress and immunity and may reveal a new mechanism by which stress can induce immunosuppression.
Source: PLoS One. 2013, 8:e74497. doi: 10.1371/journal.pone.0074497. eCollection 2013.
Read more: PLoS One
Updates
In another article, dedicated to MDSC, and their role in breast cancer, we provide a short overview and update of the recent research about the role of stress in the induction and upregulation of these cells. Here is a short summary of these new findings, more details can be found in the updates’ section of this story.
As per 2016 study stress, via catecholaminergic- and TNF-related signalling not only increases the number of MDSC and Treg cells, but in the case of MDSC also enhances their suppressive capacity. According to the authors of this study, stress-induced “emergency myelopoiesis” might promote increased innate immune activation, but may also set the stage for promoted tumor growth.
A 2021 study indicates that experimental chronic restraint stress promotes carcinoma (HCC) growth, as well as the mobilization of MDSCs to spleen and tumor sites from bone marrow. The study also provides evidence that catecholamines mediate the mobilization and immunosuppressive function of MDSCs via CXCL5-CXCR2-Erk signaling, linking psychological stress with the enhanced tumor progression.
Another 2021 study indicates that the pre-exposure of chronic stress contributes to MDSCs elevation and facilitated breast cancer metastasis in tumor-bearing mice. The study indicated that chronic stress may accumulate MDSCs via activation of β-adrenergic signaling and IL-6/STAT3 pathway, thereby promoting breast carcinoma metastasis (see the schematic figure in the breast cancer-related story). Importantly, the authors of this study discuss that the sympathetic nerves’ regulation of MDSCs mobilization may provide potential cellular and molecular mechanisms for clinical studies linking chronic stress to increased breast cancer progression in humans.
