bims-stacyt 2019-01-27 papers

Eur J Pharmacol. 2019 Jan 22. pii: S0014-2999(19)30055-X. [Epub ahead of print]

Mesenchymal stromal cells-derived exosomes alleviate ischemia/reperfusion injury in mouse lung by transporting anti-apoptotic miR-21-5p.

Ji Wei Li, Li Wei, Zhijun Han, Zhong Chen.

MiR-21-5p is an anti-apoptotic miRNA known to mediate the protective effect of mesenchymal stromal cell-secreted exosomes (MSC-Exo) against oxidative stress-induced cell death. In the present research we employed murine lung ischemia/reperfusion (I/R) model and in vitro hypoxia/reoxygenation (H/R) model using primary murine pulmonary endothelial cells to investigate whether MSC-Exo could alleviate lung IRI by transporting miR-21-5p. Our data suggested that intratracheal administration of MSC-Exo or miR-21-5p agomir significantly reduced lung edema and dysfunction, M1 polarization of alveolar macrophages as well as secretion of HMGB1, IL-8, IL-1β, IL-6, IL-17 and TNF-α. Pre-challenge of MSCs by H/R significant increased miR-21-5p expression level in exosomes they secreted and the anti-IRI effect of these MSC-Exo, while pre-treatment of MSCs with miR-21-5p antagomir showed opposite effect. We further demonstrated that MSC-Exo ameliorated IRI in vivo or H/R induced apoptosis in vitro by inhibiting both intrinsic and extrinsic apoptosis pathway via miR-21-5p targeting PTEN and PDCD4, while artificial overexpressing PTEN or PDCD4 significantly attenuated the anti-apoptotic effect of MSC-Exo in vitro. Treatment with miR-21-5p agomir mimicked the IRI-reducing and anti-apoptotic effect of MSC-Exo. Our data suggested that MSC-Exo alleviate IRI in lung in an exosomal miR-21-5p-dependent manner. Treatment with MSC-Exo or miR-21-5p agomir might ameliorate IRI in lung.

Keywords: apoptosis; exosomes; ischemia/reperfusion injury; mesenchymal stromal cells; miR-21-5p

DOI: https://doi.org/10.1016/j.ejphar.2019.01.022

Immunotherapy. 2019 Mar;11(4): 335-345

Metabolic regulation of CAR T cell function by the hypoxic microenvironment in solid tumors.

Anna Schurich, Isabelle Magalhaes, Jonas Mattsson.

The field of immunometabolism has attracted growing attention as an area at the heart of immune regulation. Upon activation, T cells undergo significant metabolic changes allowing them to mediate effector responses. The advent of chimeric antigen receptor T cell-adoptive therapy has shown some striking clinical efficacy but fails to induce sufficient antitumor response in many patients. Solid tumors put up significant opposition creating a microenvironment deficient of oxygen and glucose, depriving T cells of energy and pushing them to exhaustion. Here, we focus on immune suppressive mechanisms related to hypoxia in the tumor microenvironment and the resulting metabolic changes in T cells. New therapeutic approaches such as generating chimeric antigen receptor T cells able to withstand the challenging solid tumor microenvironment are needed.

Keywords: CAR T cells; T cell engineering; T cell exhaustion; cancer therapy; hypoxia; metabolism; tumor microenvironment

DOI: https://doi.org/10.2217/imt-2018-0141

Leukemia. 2019 Jan 24.

Inflammation-induced glycolytic switch controls suppressivity of mesenchymal stem cells via STAT1 glycosylation.

R Jitschin, M Böttcher, D Saul, S Lukassen, H Bruns, R Loschinski, A B Ekici, A Reis, A Mackensen, D Mougiakakos.

Mesenchymal stem cells (MSCs) represent key contributors to tissue homeostasis and promising therapeutics for hyperinflammatory conditions including graft-versus-host disease. Their immunomodulatory effects are controlled by microenvironmental signals. The MSCs' functional response towards inflammatory cues is known as MSC-"licensing" and includes indoleamine 2,3-dioxygenase (IDO) upregulation. MSCs use tryptophan-depleting IDO to suppress T-cells. Increasing evidence suggests that several functions are (co-)determined by the cells' metabolic commitment. MSCs are capable of both, high levels of glycolysis and of oxidative phosphorylation. Although several studies have addressed alterations of the immune regulatory phenotype elicited by inflammatory priming metabolic mechanisms controlling this process remain unknown. We demonstrate that inflammatory MSC-licensing causes metabolic shifts including enhanced glycolysis and increased fatty acid oxidation. Yet, only interfering with glycolysis impacts IDO upregulation and impedes T-cell-suppressivity. We identified the Janus kinase (JAK)/signal transducer and activator of transcription (STAT)1 pathway as a regulator of both glycolysis and IDO, and show that enhanced glucose turnover is linked to abundant STAT1 glycosylation. Inhibiting the responsible O-acetylglucosamine (O-GlcNAc) transferase abolishes STAT1 activity together with IDO upregulation. Our data suggest that STAT1-O-GlcNAcylation increases its stability towards degradation thus sustaining downstream effects. This pathway could represent a target for interventions aiming to enhance the MSCs' immunoregulatory potency.

DOI: https://doi.org/10.1038/s41375-018-0376-6