Psychological stress – expansion of immature monocytes
A recent study by Nicole Powell et al. published in the October 8, 2013 issue of PNAS, suggests that stress hormones may contribute to pro-inflammation through selective expansion and/or recruitment of a specific subpopulation of immature, proinflammatory monocytes.
In the 1970s and 1980s stress was often considered immunosuppressive. Recent evidence, however, indicates that psychological stress influences immunity in a less monochromatic way, but at multiple levels and can be in either direction, in terms of its pro- or anti-inflammatory effects.
One mechanism of how stress may boost inflammation – is through the effects of stress hormones on the induction of migration and recruitment of immune cells.
In fact, stress hormones such as catecholamines (the end products of the sympathetic nervous system) are able to modify the circulation and cell trafficking of virtually all immune cells, such as lymphocytes, polymorphonuclear cells, monocytes, dendritic cells and NK cells.
The bone marrow is extensively innervated. Previous research indicates that in the bone marrow, catecholamines originate mostly from the sympathetic nerve fibers, and myelopoiesis is negatively affected by α1-adrenoreceptors expressed on bone marrow cells (Maestroni GJ et al., Blood. 1992, 80:1178).
The PNAS study of Powell et al. demonstrates the ability of the sympathetic nervous system, through a β-adrenoreceptor-mediated mechanism to increase the myelopoietic output of immature proinflammatory monocytes (Ly-6chigh in mice and CD14+/CD16− in humans).
According to the authors this mechanism may have evolved to help the immune system anticipate wound-related bacterial infections, however, in contemporary social environments, it may promote chronic inflammation.
Thus, taken as a whole, the study may identify an additional mechanism by which adverse social environments and stress can enhance the risk of inflammation-related diseases in susceptible individuals.
Source: Proc Natl Acad Sci U S A, 2013, 110:16574-9. doi: 10.1073/pnas.1310655110. Epub 2013 Sep 23
Read More: pnas.org
Updates
A 2017 PLOS One study reports that chronic and acute academic stress is related to a reduction in the absolute numbers of natural killer (NK) cells and monocytes in peripheral blood and a shift towards more immature and naïve cells within NK and T cell populations. In addition, IL-6 and TNF-α production by LPS-stimulated monocytes was increased.
The decrease in the absolute numbers of NK cells is consistent with previous studies and has been associated with chronic stress. However, the shift from mature to more immature NK cell subpopulations in peripheral blood has not been reported so far. This suggests that the brief naturalistic stressor results in a redistribution of specific lymphocyte subsets.
The reduction in monocyte numbers could similarly be a result of the redistribution of these cells from the blood into the tissue. However, we also detected an increased functionality of these cells. Therefore, despite lower monocyte numbers we detected more LPS-induced production of IL-6 and TNF-α in response to the examination stress. Therefore, a brief naturalistic stressor may boost the functionality of monocytes.
Monocyte responses are important for immune reactions against bacterial infections and NK cells and cytotoxic T cells are necessary for the defense against viral infections. Therefore, the redistribution of these cells towards possible sites of injury and infection and the enhanced function of monocytes may be a way to boost the immune system in response to the brief stressor and to protect the individual from infections.
A 2021 study published in the Open Access Journal Cell Reports provides evidence that stress induces a hyperinflammatory state in the myeloid cells of mice and humans, which is characterized by broad changes in chromatin architecture at inflammatory and metabolic gene loci, increased inflammatory gene expression, and augmented cytokine production upon secondary challenge.
Interestingly, in humans, subjects with high stress had higher white blood cell (WBC) counts, with absolute higher counts for neutrophils and monocytes. In addition, the neutrophil:lymphocyte ratio and the monocyte:lymphocyte ratio, markers of subclinical inflammation, were higher in subjects with high stress compared to subjects with low stress.
Chronic stress induces the Akt-mTOR-HIF-1 and interferon (IFN) signaling pathways known to be critical mediators of the metabolic and epigenetic rewiring of myeloid cells. IFN, a known mediator of epigenetic changes at inflammatory loci, was the top canonical pathway enriched in both humans and mice.
The study identified a strong signature of IFN-stimulated gene expression in both stressed mice and humans, with both type I (IFN-α, IFN-β) and type II (IFN-γ) IFNs predicted to be upstream regulators. Overall, these results indicate that like microbial danger signals, chronic stress imprints priming that confers a hyperresponsive state.
A 2023 study published in Cell reports that chronically elevated levels of glucocorticoids drive the generation of an inflammatory subset of enteric glia that promotes monocyte- and TNF-mediated inflammation via colony stimulating factor 1 (CSF1). Additionally, glucocorticoids cause transcriptional immaturity in enteric neurons, acetylcholine deficiency, and dysmotility via TGF-β2.
The study suggest that psychological stress alters the landscape of intestinal myeloid cells, results in accumulation of inflammatory monocytes, and leads to TNF-mediated colitis exacerbation. Also, more in details, the data suggest a model whereby chronic stress results in glucocorticoid exposure of enteric glia and the generation of eGAPS. Enteric glia, in turn, promote the accumulation of TNF-producing monocytes via CSF1 and enhance inflammatory responses to a colitogenic insult.
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