Human Anti-Inflammatory Macrophages Induce Foxp3+GITR+CD25+ Regulatory T Cells, Which Suppress via Membrane-Bound TGFβ-1

Savage, Nigel D. L.; Boer, Tjitske de; Walburg, Kimberley V.; Joosten, Simone A.; Meijgaarden, Krista E. van; Geluk, Annemiek; Ottenhoff, Tom H. M.

doi:10.4049/jimmunol.181.3.2220

Cited by 226 publications

(181 citation statements)

References 32 publications

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“…This effect might be potentiated in vivo, because NOD-Tg bGH cells are continuously exposed to high levels of circulating GH. Treg cells in vivo might also be activated locally by antigen-presenting cells (37) specifically charged with islet antigens, which were absent in our in vitro experiments.…”

Section: Nod-tg Bgh Mice Have Normal Delayed Type Hypersensitivitymentioning

confidence: 87%

“…These differences might be considered insufficient to explain complete resistance to diabetes development; nonetheless, T-cell differentiation and activity are dependent on antigenpresenting cell type and the microenvironment in which presentation occurs, and Treg cells might be induced only locally by M2 macrophages (37). Macrophages have two distinct phenotypes (54): inflammatory (M1) macrophages participate in antigen recognition and secretion of inflammatory cytokines, and noninflammatory (M2) macrophages are involved in tissue repair and remodeling (55).…”

Section: Discussionmentioning

confidence: 99%

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Growth hormone prevents the development of autoimmune diabetes

Villares

Kakabadse

Juarranz

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Evidence supports a relationship between the neuroendocrine and the immune systems. Data from mice that overexpress or are deficient in growth hormone (GH) indicate that GH stimulates T and B-cell proliferation and Ig synthesis, and enhances maturation of myeloid progenitor cells. The effect of GH on autoimmune pathologies has nonetheless been little studied. Using a murine model of type 1 diabetes, a T-cell-mediated autoimmune disease characterized by immune cell infiltration of pancreatic islets and destruction of insulin-producing β-cells, we observed that sustained GH expression reduced prodromal disease symptoms and eliminated progression to overt diabetes. The effect involves several GH-mediated mechanisms; GH altered the cytokine environment, triggered anti-inflammatory macrophage (M2) polarization, maintained activity of the suppressor T-cell population, and limited Th17 cell plasticity. In addition, GH reduced apoptosis and/or increased the proliferative rate of β-cells. These results support a role for GH in immune response regulation and identify a unique target for therapeutic intervention in type 1 diabetes.beta cells | Tregs G rowth hormone (GH) is a pleiotropic hormone that affects a broad spectrum of physiological functions, from carbohydrate and lipid metabolism to the immune response (1). Several studies have linked GH with autoimmune diseases, although its effects on the immune system are still debated. Whereas some reports using GH-deficient mice indicate that it does not affect immune competence (2), others suggest that GH is necessary for correct immune system development (1, 3). The GH receptor (GHR) is expressed by several lymphocyte subpopulations (4). GH stimulates in vitro T and B-cell proliferation (5) and Ig synthesis (6); enhances human myeloid progenitor cell maturation (7); and modulates in vivo Th1/Th2 (8) and humoral immune responses (1). In addition, therapeutic activation of the GH/STAT5B axis is postulated as a target for restoring mucosal tolerance in Crohn disease (9, 10). A single point mutation in STAT5B limits its DNA binding activity as well as maintenance of FOXP3 expression by Treg cells in nonobese diabetic (NOD) mice (11). These mice develop type 1 diabetes, which is characterized by autoimmune destruction of pancreatic β-cells due to the effect of environmental factors on genetically predisposed individuals (12,13). Although this murine model does not completely mimic the human disease, most steps in the pathogenesis, including prodromal and clinical symptoms, are closely comparable (14).Despite the interdependence of GH and insulin regulation and the known effects of GH and insulin-like growth factor 1 (IGF1) on pancreatic β-cell survival, proliferation and neogenesis (15, 16), hormone influences have not been described in type 1 diabetes; no specific studies have addressed the consequences of long-term GH replacement therapy in this disease. Here we show the effects of long-term GH supplementation as a tool to modulate autoimmune attack on pancreatic β-cells. NOD...

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Section: Nod-tg Bgh Mice Have Normal Delayed Type Hypersensitivitymentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Growth hormone prevents the development of autoimmune diabetes

Villares

Kakabadse

Juarranz

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…1). M2 cells were shown to induce differentiation of regulatory T cells [26]; conversely, regulatory T cells have been reported to induce alternative activation of human mononuclear phagocytes [27]. While general properties are retained from mouse to man, there are significant differences, such as the association of YM1, Fizz1 and Arginase 1 with M2 polarization in the mouse but not in man [18].…”

Section: Activation and Adaptive Responses Of Macrophagesmentioning

confidence: 99%

From phagocyte diversity and activation to probiotics: Back to Metchnikoff

Mantovani

2008

Eur J Immunol

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In this issue of the European Journal of Immunology, Siamon Gordon gives a detailed account of Metchnikoff's life and his achievements (Eur. J. Immunol. 2008. 38: 3257-3264). Looking back at the roots of innate immunity stimulates reflections on open issues in the field. Here, I give a personal view of some of these issues, including myeloid-derived suppressor cells, macrophage polarization and adaptive responses of mononuclear phagocytes. Key words: Macrophage activation Á Macrophages Á M1/M2 polarization Á Probiotics See accompanying article by Gordon IntroductionIn his scholarly review [1], Siamon Gordon tracks the roots of innate immunity to Elie Metchnikoff. The essay provides a fascinating insight into Metchnikoff's scientific life and how he tackled fundamental issues in science, some of which remain with us to this day. The perspective offered by a major player in the very same field of phagocytes and innate immunity [2,3] adds flavour and fascination to this article not necessarily present in other accounts [4]. Such a reflection on a central part of modern immunology stimulates consideration of remaining open issues and there follows a personal view of some of these.Phagocyte heterogeneity: From microphage-macrophage dichotomy to myeloid-derived suppressor cellsThe fundamental distinction between polymorphonuclear leukocytes (microphages) and mononuclear phagocytes (macrophages) was a major first step in the dissection of phagocyte heterogeneity and lineage differentiation. The identification of myeloid-derived suppressor cells (MDSC) [5][6][7] raises the questions whether the classic sharp distinction between the myeloid and the monocyte-macrophage differentiation and activation pathways is appropriate. In contrast to long-held views, neutrophils express specific transcriptional programmes in response to environmental signals [8]. MDSC include immature myeloid precursors that can further differentiate, and play a key role in the suppression of adaptive immunity in diverse pathological conditions ranging from cancer to chronic infections [5][6][7]. Are we dealing with a blurring of a classic distinction or with a well-defined third phagocyte population? Using current identification and separation criteria (e.g. Gr1, CD11b, F4/80) MDSC in the blood and lymphoid organs are a mixed population, which includes myeloid cells at different stages of differentiation and mononuclear phagocytes. Thus, the definition of MDSC remains an operational one rather than that of a cell type, a reality that is frequently neglected. The issue of lineage of the actual effectors of MDSC-mediated suppression is even more relevant when their recruitment and activation in non-lymphoid tissues is considered. For instance, do MDSC retain an immature phenotype in tumour tissues or do they differentiate into tumourassociated macrophages [9][10][11] [9,12,16,17], bacterial [43][44][45][46][47][48][49] and parasitic [50][51][52][53] infections. Evidence has also accumulated that polarized macrophages are more than mere spectators of i...

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“…Increased IL-10 secretion is a characteristic of type II activated macrophages, which have an immunomodulatory, anti-inflammatory function. 36,37 Type-II-activated macrophages have also been shown to be able to induce regulatory T cells, 38 another potential additional indirect immunomodulatory effect of MSC.…”

Section: Cd1amentioning

confidence: 99%

Multipotent stromal cells skew monocytes towards an anti-inflammatory interleukin-10-producing phenotype by production of interleukin-6

et al. 2013

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Multipotent stromal cells have immunomodulatory capacities and have been used in transplantation and autoimmune diseases. One of the effects of multipotent stromal cells involves the inhibition of dendritic cell differentiation. Since interleukin-6 and interleukin-10 are known to play a role in inhibiting immature dendritic cell differentiation, we hypothesized that these cytokines may also mediate the inhibitory effect of human multipotent stromal cells in immature dendritic cell differentiation. In order to test this hypothesis monocytes were cultured with interleukin-4 and granulocyte-monocyte colony-stimulating factor in the presence or absence of culture-expanded bone marrow-derived multipotent stromal cells. Neutralization and cytokine-depletion strategies were applied to reveal the cellular source and effect of interleukin-6 and interleukin-10. Addition of multipotent stromal cells to monocyte cultures significantly reduced the generation of immature dendritic cells (CD14 -CD1a + ) and resulted in the generation of CD14 + CD1a -cells that displayed a significantly reduced immunostimulatory effect. We found that culture supernatants of co-cultures of multipotent stromal cells and monocytes contained higher concentrations of interleukin-6 and interleukin-10. Multipotent stromal cells produced interleukin-6 and neutralizing this interleukin-6 reversed the inhibitory effect of the multipotent cells. Interleukin-10 was not produced by multipotent stromal cells, but exclusively by monocytes after exposure to multipotent stromal cell-produced interleukin-6. In conclusion, through constitutive production of interleukin-6, multipotent stromal cells prevent the differentiation of monocytes towards antigen-presenting immunogenic cells and skew differentiation towards an antiinflammatory interleukin-10-producing cell type.Multipotent stromal cells skew monocytes towards an anti-inflammatory interleukin-10-producing phenotype by production of interleukin-6 Sara M. Melief, Sacha B. Geutskens, Willem E. Fibbe, and Helene Roelofs Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands ABSTRACT Introduction

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Human Anti-Inflammatory Macrophages Induce Foxp3+GITR+CD25+ Regulatory T Cells, Which Suppress via Membrane-Bound TGFβ-1

Cited by 226 publications

References 32 publications

Growth hormone prevents the development of autoimmune diabetes

Growth hormone prevents the development of autoimmune diabetes

From phagocyte diversity and activation to probiotics: Back to Metchnikoff

Multipotent stromal cells skew monocytes towards an anti-inflammatory interleukin-10-producing phenotype by production of interleukin-6

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