Pharmacological modulation of myeloid-derived suppressor cells to dampen inflammation

Abstract

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous cell population with potent suppressive and regulative properties. MDSCs' strong immunosuppressive potential creates new possibilities to treat chronic inflammation and autoimmune diseases or induce tolerance towards transplantation. Here, we summarize and critically discuss different pharmacological approaches which modulate the generation, activation, and recruitment of MDSCs in vitro and in vivo, and their potential role in future immunosuppressive therapy.

Keywords: MDSC; immune suppression; immunomodulation; inflammation; pharmacotherapy.

Figure 1

Mechanisms of possible pharmacological targets for the induction of MDSCs. Proliferation and activation of MDSCs is regulated by transcription factors such as signal transducer and activator of transcription (STAT) 3, STAT1, STAT5, STAT6 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). In vitro generation of MDSCs is induced by a large variety of cytokines and cytokine combinations and lactoferrin. MDSC generation may be followed by adoptive transfer cell therapy to induce the beneficial effects of MDSCs. Various compounds [e.g. rapamycin, glucocorticoids, terbutaline, tofacitinib, glatirameracetat, cannabidiol, clarithromycin, taurodeoxycholate, CXCR1 or CXCR2 ligands, complete Freund’s adjuvant (CFA), membrane vesicles (MV), Toll-like receptor (TLR) 2/4 agonistic antibodies, prostaglandin E₂, cyclosporine A and receptor interacting protein kinase (RIPK) 3 inhibitor (GSK 872)] may be used for accumulation of MDSCs in vivo. G-CSF granulocyte colony-stimulating factor, M-CSF macrophage CSF, GM-CSF granulocyte-macrophage CSF, IL Interleukin, TNF tumor necrosis factor, TGF transforming growth factor, VEGF vascular endothelial growth factor, IFN interferon, mTOR mammalian target of rapamycin, JAK Janus kinase, LRP lactoferrin receptor, iNOS inducible nitric oxide synthase, Arg arginase, IDO indoleamine 2,3-dioxygenase, NADPH nicotiamide adenine dinucleotide phosphate, NFAT nuclear factor of activated t cells, p phosphorylated, CXCR CXC chemokine receptors, COX cyclooxygenase.