Chronic restraint stress promotes the mobilization and recruitment of myeloid‐derived suppressor cells through β‐adrenergic‐activated CXCL5‐CXCR2‐Erk signaling cascades

Abstract

Myeloid-derived suppressor cells (MDSCs) play an important role in tumor immune escape. Recent studies have shown that MDSCs contribute to tumor progression under psychological stress, but the underlying mechanism of MDSCs mobilization and recruitment remains largely unknown. In the present study, a chronic restraint stress paradigm was applied to the H22 hepatocellular carcinoma (HCC) bearing mice to mimic the psychological stress. We observed that chronic restraint stress significantly promoted HCC growth, as well as the mobilization of MDSCs to spleen and tumor sites from bone marrow. Meanwhile, chronic restraint stress enhanced the expression of C-X-C motif chemokine receptor 2 (CXCR2) and pErk1/2 in bone marrow MDSCs, together with elevated chemokine (C-X-C motif) ligand 5 (CXCL5) expression in tumor tissues. In vitro, the treatments of MDSCs with epinephrine (EPI) and norepinephrine (NE) but not corticosterone (CORT)-treated H22 conditioned medium obviously inhibited T-cell proliferation, as well as enhanced CXCR2 expression and extracellular signal-regulated kinase (Erk) phosphorylation. In vivo, β-adrenergic blockade with propranolol almost completely reversed the accelerated tumor growth induced by chronic restraint stress and inactivated CXCL5-CXCR2-Erk signaling pathway. Our findings support the crucial role of β-adrenergic signaling cascade in the mobilization and recruitment of MDSCs under chronic restraint stress.

Impact of Lipid Metabolism on Antitumor Immune Response

“…There is evidence that CD8+ T cells have their activity drastically suppressed by MDSCs with high lipid overload as opposed to MDSCs with normal lipid content. This lipid accumulation can be associated with an elevated FA uptake, as demonstrated by Cao et al, who showed that upregulation of fatty acid transport protein 4 (FATP4) expression was observed in tumor-derived MDSCs [ 51 ]. MDSCs can be divided into two different subtypes: monocytic (M) and polymorphonuclear (PMN).…”

“…Another group of researchers indicated that culturing a myeloid-suppressor cell line (MSC-2) in the presence of sodium oleate, a long-chain, unsaturated FA, induced an increased lipid droplet accumulation and thereby upregulated their immune-suppression function [ 57 ]. Moreover, Cao et al found that treatment of MDSCs with linoleic acid, another unsaturated FA, makes them more immunosuppressive than those treated with palmitic acid [ 51 ].…”

Chronic stress promotes breast carcinoma metastasis by accumulating myeloid-derived suppressor cells through activating β-adrenergic signaling

“…Recent reports showed that catecholamines could regulate MDSCs’ development, mobilization, and trafficking through β-ARs. 37 , 38 In current study, treatment with β3-AR selective blocker SR59230A failed to alleviate stress-induced tumor metastasis and MDSCs’ response in tumor-bearing mice; however, treatment with β1-AR/β2-AR inhibitor propranolol could reduce the number of CD11b + Gr-1 + cells in circulation, suppress MDSCs infiltration into lung tissues and attenuate tumor metastasis caused by chronic stress. There may be a close link between β1/β2-AR activation and MDSCs’ trafficking in tumor-bearing mice.…”

The dynamic changes of cellular immunity among frontline medical workers who supported Wuhan for fighting against the COVID-19

“…Psychological stress has great impact on immune system through activating nervous system [25] , [26] , [27] . Previous studies indicated that psychological stress regulates the redistribution of leukocytes through stress responses by activating the SNS and HPA axis, which release catecholaminergic neurotransmitters and corticosterone [12] , [13] , [28] , [29] . In this study, we found that the LYM count and LYM ratio increased while the MONO ratio, NLR, MLR and NEUT ratio in the peripheral blood of frontline medical workers decreased 10 days post-stress.…”