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      Arginase-1–dependent promotion of T H17 differentiation and disease progression by MDSCs in systemic lupus erythematosus

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          Abstract

          Expansion of myeloid-derived suppressor cells (MDSCs) has been documented in some murine models and patients with autoimmune diseases, but the exact role of MDSCs in this process remains largely unknown. The current study investigates this question in patients with systemic lupus erythematosus (SLE). Patients with active SLE showed a significant increase in HLA-DR CD11b +CD33 + MDSCs, including both CD14 +CD66b monocytic and CD14 CD66b + granulocytic MDSCs, in the peripheral blood compared to healthy controls (HCs). The frequency of MDSCs was positively correlated with the levels of serum arginase-1 (Arg-1) activity, T helper 17 (T H17) responses, and disease severity in SLE patients. Consistently, in comparison with MDSCs from HCs, MDSCs from SLE patients exhibited significantly elevated Arg-1 production and increased potential to promote T H17 differentiation in vitro in an Arg-1–dependent manner. Moreover, in a humanized SLE model, MDSCs were essential for the induction of T H17 responses and the associated renal injuries, and the effect of MDSCs was Arg-1–dependent. Our data provide direct evidence demonstrating a pathogenic role for MDSCs in human SLE. This study also provides a molecular mechanism of the pathogenesis of SLE by demonstrating an Arg-1–dependent effect of MDSCs in the development of T H17 cell–associated autoimmunity, and suggests that targeting MDSCs or Arg-1 may offer potential therapeutic strategies for the treatment of SLE and other T H17 cell–mediated autoimmune diseases.

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          Most cited references50

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          T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma.

          T cell functional differentiation is mediated by lineage-specific transcription factors. T helper 17 (Th17) has been recently identified as a distinct Th lineage mediating tissue inflammation. Retinoic acid receptor-related orphan receptor gamma (ROR gamma) was shown to regulate Th17 differentiation; ROR gamma deficiency, however, did not completely abolish Th17 cytokine expression. Here, we report Th17 cells highly expressed another related nuclear receptor, ROR alpha, induced by transforming growth factor-beta and interleukin-6 (IL-6), which is dependent on signal transducer and activator of transcription 3. Overexpression of ROR alpha promoted Th17 differentiation, possibly through the conserved noncoding sequence 2 in Il17-Il17f locus. ROR alpha deficiency resulted in reduced IL-17 expression in vitro and in vivo. Furthermore, ROR alpha and ROR gamma coexpression synergistically led to greater Th17 differentiation. Double deficiencies in ROR alpha and ROR gamma globally impaired Th17 generation and completely protected mice against experimental autoimmune encephalomyelitis. Therefore, Th17 differentiation is directed by two lineage-specific nuclear receptors, ROR alpha and ROR gamma.
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            The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat.

            T(H)-17 cells are interleukin 17 (IL-17)-secreting CD4+ T helper cells involved in autoimmune disease and mucosal immunity. In naive CD4+ T cells from mice, IL-17 is expressed in response to a combination of IL-6 or IL-21 and transforming growth factor-beta (TGF-beta) and requires induction of the nuclear receptor RORgammat. It has been suggested that the differentiation of human T(H)-17 cells is independent of TGF-beta and thus differs fundamentally from that in mice. We show here that TGF-beta, IL-1beta and IL-6, IL-21 or IL-23 in serum-free conditions were necessary and sufficient to induce IL-17 expression in naive human CD4+ T cells from cord blood. TGF-beta upregulated RORgammat expression but simultaneously inhibited its ability to induce IL-17 expression. Inflammatory cytokines relieved this inhibition and increased RORgammat-directed IL-17 expression. Other gene products detected in T(H)-17 cells after RORgammat induction included the chemokine receptor CCR6, the IL-23 receptor, IL-17F and IL-26. Our studies identify RORgammat as having a central function in the differentiation of human T(H)-17 cells from naive CD4+ T cells and suggest that similar cytokine pathways are involved in this process in mice and humans.
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              Arginine metabolism and nutrition in growth, health and disease.

              L-Arginine (Arg) is synthesised from glutamine, glutamate, and proline via the intestinal-renal axis in humans and most other mammals (including pigs, sheep and rats). Arg degradation occurs via multiple pathways that are initiated by arginase, nitric-oxide synthase, Arg:glycine amidinotransferase, and Arg decarboxylase. These pathways produce nitric oxide, polyamines, proline, glutamate, creatine, and agmatine with each having enormous biological importance. Arg is also required for the detoxification of ammonia, which is an extremely toxic substance for the central nervous system. There is compelling evidence that Arg regulates interorgan metabolism of energy substrates and the function of multiple organs. The results of both experimental and clinical studies indicate that Arg is a nutritionally essential amino acid (AA) for spermatogenesis, embryonic survival, fetal and neonatal growth, as well as maintenance of vascular tone and hemodynamics. Moreover, a growing body of evidence clearly indicates that dietary supplementation or intravenous administration of Arg is beneficial in improving reproductive, cardiovascular, pulmonary, renal, gastrointestinal, liver and immune functions, as well as facilitating wound healing, enhancing insulin sensitivity, and maintaining tissue integrity. Additionally, Arg or L-citrulline may provide novel and effective therapies for obesity, diabetes, and the metabolic syndrome. The effect of Arg in treating many developmental and health problems is unique among AAs, and offers great promise for improved health and wellbeing of humans and animals.
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                Author and article information

                Journal
                101505086
                36963
                Sci Transl Med
                Sci Transl Med
                Science translational medicine
                1946-6234
                1946-6242
                27 May 2016
                23 March 2016
                23 March 2017
                : 8
                : 331
                : 331ra40
                Affiliations
                [1 ]The First Hospital and Institute of Immunology, Jilin University, Changchun 130061, China
                [2 ]Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
                [3 ]Department of Medicine, Columbia Center for Translational Immunology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA
                Author notes
                [* ]Corresponding author. yihuanfa@ 123456jlu.edu.cn (H.Y.); yy2324@ 123456columbia.edu (Y.-G.Y.)
                Article
                PMC4895207 PMC4895207 4895207 nihpa790036
                10.1126/scitranslmed.aae0482
                4895207
                27009269
                ce08f0f3-e63e-4301-9b28-80ee2b73d9ff
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