GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans.

GDF15 is an established biomarker of cellular stress. The fact that it signals via a specific hindbrain receptor, GFRAL, and that mice lacking GDF15 manifest diet-induced obesity suggest that GDF15 may play a physiological role in energy balance. We performed experiments in humans, mice, and cells to determine if and how nutritional perturbations modify GDF15 expression. Circulating GDF15 levels manifest very modest changes in response to moderate caloric surpluses or deficits in mice or humans, differentiating it from classical intestinally derived satiety hormones and leptin. However, GDF15 levels do increase following sustained high-fat feeding or dietary amino acid imbalance in mice. We demonstrate that GDF15 expression is regulated by the integrated stress response and is induced in selected tissues in mice in these settings. Finally, we show that pharmacological GDF15 administration to mice can trigger conditioned taste aversion, suggesting that GDF15 may induce an aversive response to nutritional stress.This work and authors were funded by the NIHR Cambridge Biomedical Research Centre; NIHR Rare Disease Translational Research Collaboration; Medical Research Council [MC_UU_12012/2 and MRC_MC_UU_12012/3]; MRC Metabolic Diseases Unit [MRC_MC_UU_12012/5 and MRC_MC_UU_12012.1]; Wellcome Trust Strategic Award [100574/Z/12/Z and 100140]; Wellcome Trust [107064 , 095515/Z/11/Z , 098497/Z/12/Z, 106262/Z/14/Z and 106263/Z/14/Z]; British Heart Foundation [RG/12/13/29853]; Addenbrooke’s Charitable Trust / Evelyn Trust Cambridge Clinical Research Fellowship [16-69] US Department of Agriculture: 2010-34323-21052; EFSD project grant and a Royal College of Surgeons Research Fellowship, Diabetes UK Harry Keen intermediate clinical fellowship (17/0005712). European Research Council, Bernard Wolfe Health Neuroscience Endowment, Experimental Medicine Training Initiative/AstraZeneca and Medimmune

Myeloid-derived suppressor cells as a potential therapy for experimental autoimmune myasthenia gravis

We recently demonstrated that hepatic stellate cells induce the differentiation of myeloid-derived suppressor cells (MDSCs) from myeloid progenitors. In this study, we found that adoptive transfer of these MDSCs effectively reversed disease progression in experimental autoimmune myasthenia gravis (EAMG), a T-cell-dependent and B-cell-mediated model for myasthenia gravis. In addition to ameliorated disease severity, MDSC-treated EAMG mice showed suppressed acetylcholine receptors (AChR)-specific T-cell responses, decreased levels of serum anti-AChR IgGs, and reduced complement activation at the neuromuscular junctions. Incubating MDSCs with B cells activated by anti-IgM or anti-CD40 antibodies inhibited the proliferation of these in vitro activated B cells. Administering MDSCs into mice immunized with a T-cell-independent antigen inhibited the antigen-specific antibody production in vivo. MDSCs directly inhibit B cells through multiple mechanisms including prostaglandin E2, inducible nitric oxide synthase and arginase. Interestingly, MDSC treatment in EMAG mice does not appear to significantly inhibit their immune response to a non-relevant antigen, ovalbumin. These results demonstrated that hepatic stellate cell-induced MDSCs concurrently suppress both T- and B- cell autoimmunity, leading to effective treatment of established EAMG; and that the MDSCs inhibit AChR-specific immune responses at least partially in an antigen-specific manner. These data suggest that MDSCs could be further developed as a novel approach to treating myasthenia gravis and, even more broadly, other diseases in which T and B cells are involved in pathogenesis

Refertilized continental root controls the formation of the Mianning–Dechang carbonatite-associated rare-earth-element ore system

Abstract Rare earth element ore deposits associated with carbonatite derived from Earth’s mantle supply half of the world’s rare earth element. However, the formation of carbonatite and initial enrichment and transport of rare earth element in the mantle, is unclear. Here, we image the lithospheric architecture of a Cenozoic rare earth element ore belt in southwestern China by integrating seismic tomography with geochemical data. The subduction of the Indian continent caused vertical upwelling and lateral flow of the asthenosphere, which triggered the melting of the overlying subcontinental lithospheric mantle to generate carbonatites. Such a mantle source that previously metasomatized by fluids from recycled marine sediments is a precursor process critical for forming a giant rare earth element system. For the studied ore belt, three key factors are prerequisites to generating ore-forming carbonatites: thick lithosphere with a continental root; prior fertilization of the subcontinental lithospheric mantle; and trans-lithospheric weakness for magma ascent

Mesenchymal Stem Cells Inhibit Complement Activation by Secreting Factor H

Mesenchymal stem cells (MSCs) possess potent and broad immunosuppressive capabilities, and have shown promise in clinical trials treating many inflammatory diseases. Previous studies have found that MSCs inhibit dendritic cell, T-cell, and B-cell activities in the adaptive immunity; however, whether MSCs inhibit complement in the innate immunity, and if so, by which mechanism, have not been established. In this report, we found that MSCs constitutively secrete factor H, which potently inhibits complement activation. Depletion of factor H in the MSC-conditioned serum-free media abolishes their complement inhibitory activities. In addition, production of factor H by MSCs is augmented by inflammatory cytokines TNF-α and interferon-γ (IFN-γ) in dose- and time-dependent manners, while IL-6 does not have a significant effect. Furthermore, the factor H production from MSCs is significantly suppressed by the prostaglandin E2 (PGE2) synthesis inhibitor indomethacin and the indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyl-d-tryptophan (1-MT), both of which inhibitors are known to efficiently dampen MSCs immunosuppressive activity. These results indicate that MSCs inhibit complement activation by producing factor H, which could be another mechanism underlying MSCs broad immunosuppres-sive capabilities