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TRAIL modulates the immune system and protects against the development of diabetes.

Bossi F, Bernardi S, Zauli G, Secchiero P, Fabris B - J Immunol Res (2015)

Bottom Line: TRAIL or tumor necrosis factor (TNF) related apoptosis-inducing ligand is a member of the TNF superfamily of proteins, whose best characterized function is the induction of apoptosis in tumor, infected, or transformed cells through activation of specific receptors.In nontransformed cells, however, the actions of TRAIL are less well characterized.Here we review TRAIL biological actions, its effects on the immune system, and how and to what extent it has been shown to protect against diabetes.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical, Surgical, and Health Sciences, University of Trieste, Cattinara University Hospital, Strada di Fiume 447, 34100 Trieste, Italy.

ABSTRACT
TRAIL or tumor necrosis factor (TNF) related apoptosis-inducing ligand is a member of the TNF superfamily of proteins, whose best characterized function is the induction of apoptosis in tumor, infected, or transformed cells through activation of specific receptors. In nontransformed cells, however, the actions of TRAIL are less well characterized. Recent studies suggest that TRAIL may be implicated in the development and progression of diabetes. Here we review TRAIL biological actions, its effects on the immune system, and how and to what extent it has been shown to protect against diabetes.

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Related in: MedlinePlus

Current immunological view of T1DM and T2DM. (a) Islet inflammation in T1DM. A triggering insult recruits antigen-presenting cells (dendritic cells, macrophages, and B cells). Dendritic cells (DC) pick up self-antigens and immune complexes by pinocytosis and carry them to the pancreatic draining lymph nodes where they present them to autoreactive T cells and activate them. Such T cells migrate back to the islets where they destroy β-cells either by perforin, granzymes, or FasL-dependent interactions (CD8+), or by proinflammatory cytokine release (CD4+). Macrophages and B cells can also act as antigen-presenting cells. The cross-talk between B and T cells promotes the development of plasma cells, the release of autoantibodies, and the formation of immune complexes, which all together create a vicious cycle of inflammation and death. (b) TRAIL effects on islet inflammation. Experimental studies have shown that TRAIL inhibits T cell proliferation/expansion, induces T cell death, promotes Treg expansion, and protects β-cells. (c) Overview on obesity-induced insulin resistance. Obesity increases free fatty acids (FFA) that bind to toll-like receptor 4 (TLR-4) and activate adipose tissue macrophages. At the same time, the expansion of the adipose tissue, which outgrows its vascular supply, induces adipocyte necrosis, which stimulates macrophage recruitment and activation. One recruiting factor is CCL2, which mediates the recruitment of CCR2 monocytes, which differentiate into macrophages. Adipocyte death and innate immune cell activation stimulate the migration of adaptive immune cells. In addition, macrophage migration to the adipose tissue and their activation induce the expression of proinflammatory molecules, such as IL-6, MCP-1, TNF-α, and other adipokines which lead to insulin resistance. Peripheral insulin resistance is featured by impaired glucose uptake, increase of gluconeogenesis, hyperlipidemia, hyperglycemia, β-cell hypertrophy, β-cell inflammation, stress, and death. (d) TRAIL effects on obesity-induced insulin resistance. Experimental studies show that TRAIL reduces fat mass gain, systemic and tissue proinflammatory cytokines, and ameliorates peripheral insulin resistance. This is associated to a reduction of β-cell hypertrophy, inflammation, and loss.
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Related In: Results  -  Collection


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fig2: Current immunological view of T1DM and T2DM. (a) Islet inflammation in T1DM. A triggering insult recruits antigen-presenting cells (dendritic cells, macrophages, and B cells). Dendritic cells (DC) pick up self-antigens and immune complexes by pinocytosis and carry them to the pancreatic draining lymph nodes where they present them to autoreactive T cells and activate them. Such T cells migrate back to the islets where they destroy β-cells either by perforin, granzymes, or FasL-dependent interactions (CD8+), or by proinflammatory cytokine release (CD4+). Macrophages and B cells can also act as antigen-presenting cells. The cross-talk between B and T cells promotes the development of plasma cells, the release of autoantibodies, and the formation of immune complexes, which all together create a vicious cycle of inflammation and death. (b) TRAIL effects on islet inflammation. Experimental studies have shown that TRAIL inhibits T cell proliferation/expansion, induces T cell death, promotes Treg expansion, and protects β-cells. (c) Overview on obesity-induced insulin resistance. Obesity increases free fatty acids (FFA) that bind to toll-like receptor 4 (TLR-4) and activate adipose tissue macrophages. At the same time, the expansion of the adipose tissue, which outgrows its vascular supply, induces adipocyte necrosis, which stimulates macrophage recruitment and activation. One recruiting factor is CCL2, which mediates the recruitment of CCR2 monocytes, which differentiate into macrophages. Adipocyte death and innate immune cell activation stimulate the migration of adaptive immune cells. In addition, macrophage migration to the adipose tissue and their activation induce the expression of proinflammatory molecules, such as IL-6, MCP-1, TNF-α, and other adipokines which lead to insulin resistance. Peripheral insulin resistance is featured by impaired glucose uptake, increase of gluconeogenesis, hyperlipidemia, hyperglycemia, β-cell hypertrophy, β-cell inflammation, stress, and death. (d) TRAIL effects on obesity-induced insulin resistance. Experimental studies show that TRAIL reduces fat mass gain, systemic and tissue proinflammatory cytokines, and ameliorates peripheral insulin resistance. This is associated to a reduction of β-cell hypertrophy, inflammation, and loss.

Mentions: Diabetes mellitus (DM) refers to a condition of hyperglycemia that can be further classified into T1DM, primarily due to a lack of insulin, or T2DM, primarily due to peripheral insulin resistance. Whether it is T1DM or T2DM, the immune system is now recognized to be crucially involved in the development and progression of both. T1DM is in fact a T cell-mediated autoimmune disease or according to Burnet and Mackay definition, “a condition in which structural or functional damage is produced by the action of immunologically competent cells or antibodies against normal components of the body” arising by “the emergence of forbidden clones of T lymphocytes” [54]. In particular, as depicted in Figure 2(a), genetic predisposition and unknown environmental factors lead to the release of β-cell DNA and antigens that promote the recruitment of macrophages, neutrophils, DC, and B cells, as well as the formation of autoantibodies in the pancreas [55]. These autoantibodies are usually directed against insulin, insulinoma-associated antigen (IA) 2, 65-kD isoform of glutamic acid decarboxylase (GAD-65), β-cell-specific zinc transporter (Znt8), and islet cell (ICA) 512, which are not only the major autoantibody targets but also the main epitopes activating autoreactive T cells [56]. Here DC pick up antigens and immune complexes by pinocytosis and, upon activation, migrate to the pancreatic lymph nodes to present β-cell antigens to an abnormal number of autoreactive T cells, which are there because of a defective immune tolerance. Then, autoreactive T cells become fully activated and home into the islets. It has to be noted that usually T cells can be activated by the recognition of autoantigens through MHC class II on antigen-presenting cells and/or through MHC class I on β-cells [57, 58]. Then, one way or the other, activated CD8+ T cells will destroy the β-cells by the release of cytolytic granules containing perforins and granzymes or by FasL-dependent interactions, while CD4+ release proinflammatory cytokines (Figure 2(a)). At the same time, inflammation and tissue damage are further worsened by an impairment of Treg cells, which seem to be either lacking [59] and/or defective [60] in T1DM. As for the natural history of the disease, this islet inflammation (or insulitis) generally precedes T1DM onset [61] and it corresponds to the stage where autoantibodies are detectable [62]. Of note, neither autoantibodies nor B cells seem to be critically involved in T1DM pathogenesis, as T1DM can affect patients with X-linked agammaglobulinemia [63]. Anyway, when 70–80% of β-cells have been destroyed, the residual insulin-producing cells are insufficient to maintain glucose tolerance and T1DM develops [64].


TRAIL modulates the immune system and protects against the development of diabetes.

Bossi F, Bernardi S, Zauli G, Secchiero P, Fabris B - J Immunol Res (2015)

Current immunological view of T1DM and T2DM. (a) Islet inflammation in T1DM. A triggering insult recruits antigen-presenting cells (dendritic cells, macrophages, and B cells). Dendritic cells (DC) pick up self-antigens and immune complexes by pinocytosis and carry them to the pancreatic draining lymph nodes where they present them to autoreactive T cells and activate them. Such T cells migrate back to the islets where they destroy β-cells either by perforin, granzymes, or FasL-dependent interactions (CD8+), or by proinflammatory cytokine release (CD4+). Macrophages and B cells can also act as antigen-presenting cells. The cross-talk between B and T cells promotes the development of plasma cells, the release of autoantibodies, and the formation of immune complexes, which all together create a vicious cycle of inflammation and death. (b) TRAIL effects on islet inflammation. Experimental studies have shown that TRAIL inhibits T cell proliferation/expansion, induces T cell death, promotes Treg expansion, and protects β-cells. (c) Overview on obesity-induced insulin resistance. Obesity increases free fatty acids (FFA) that bind to toll-like receptor 4 (TLR-4) and activate adipose tissue macrophages. At the same time, the expansion of the adipose tissue, which outgrows its vascular supply, induces adipocyte necrosis, which stimulates macrophage recruitment and activation. One recruiting factor is CCL2, which mediates the recruitment of CCR2 monocytes, which differentiate into macrophages. Adipocyte death and innate immune cell activation stimulate the migration of adaptive immune cells. In addition, macrophage migration to the adipose tissue and their activation induce the expression of proinflammatory molecules, such as IL-6, MCP-1, TNF-α, and other adipokines which lead to insulin resistance. Peripheral insulin resistance is featured by impaired glucose uptake, increase of gluconeogenesis, hyperlipidemia, hyperglycemia, β-cell hypertrophy, β-cell inflammation, stress, and death. (d) TRAIL effects on obesity-induced insulin resistance. Experimental studies show that TRAIL reduces fat mass gain, systemic and tissue proinflammatory cytokines, and ameliorates peripheral insulin resistance. This is associated to a reduction of β-cell hypertrophy, inflammation, and loss.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig2: Current immunological view of T1DM and T2DM. (a) Islet inflammation in T1DM. A triggering insult recruits antigen-presenting cells (dendritic cells, macrophages, and B cells). Dendritic cells (DC) pick up self-antigens and immune complexes by pinocytosis and carry them to the pancreatic draining lymph nodes where they present them to autoreactive T cells and activate them. Such T cells migrate back to the islets where they destroy β-cells either by perforin, granzymes, or FasL-dependent interactions (CD8+), or by proinflammatory cytokine release (CD4+). Macrophages and B cells can also act as antigen-presenting cells. The cross-talk between B and T cells promotes the development of plasma cells, the release of autoantibodies, and the formation of immune complexes, which all together create a vicious cycle of inflammation and death. (b) TRAIL effects on islet inflammation. Experimental studies have shown that TRAIL inhibits T cell proliferation/expansion, induces T cell death, promotes Treg expansion, and protects β-cells. (c) Overview on obesity-induced insulin resistance. Obesity increases free fatty acids (FFA) that bind to toll-like receptor 4 (TLR-4) and activate adipose tissue macrophages. At the same time, the expansion of the adipose tissue, which outgrows its vascular supply, induces adipocyte necrosis, which stimulates macrophage recruitment and activation. One recruiting factor is CCL2, which mediates the recruitment of CCR2 monocytes, which differentiate into macrophages. Adipocyte death and innate immune cell activation stimulate the migration of adaptive immune cells. In addition, macrophage migration to the adipose tissue and their activation induce the expression of proinflammatory molecules, such as IL-6, MCP-1, TNF-α, and other adipokines which lead to insulin resistance. Peripheral insulin resistance is featured by impaired glucose uptake, increase of gluconeogenesis, hyperlipidemia, hyperglycemia, β-cell hypertrophy, β-cell inflammation, stress, and death. (d) TRAIL effects on obesity-induced insulin resistance. Experimental studies show that TRAIL reduces fat mass gain, systemic and tissue proinflammatory cytokines, and ameliorates peripheral insulin resistance. This is associated to a reduction of β-cell hypertrophy, inflammation, and loss.
Mentions: Diabetes mellitus (DM) refers to a condition of hyperglycemia that can be further classified into T1DM, primarily due to a lack of insulin, or T2DM, primarily due to peripheral insulin resistance. Whether it is T1DM or T2DM, the immune system is now recognized to be crucially involved in the development and progression of both. T1DM is in fact a T cell-mediated autoimmune disease or according to Burnet and Mackay definition, “a condition in which structural or functional damage is produced by the action of immunologically competent cells or antibodies against normal components of the body” arising by “the emergence of forbidden clones of T lymphocytes” [54]. In particular, as depicted in Figure 2(a), genetic predisposition and unknown environmental factors lead to the release of β-cell DNA and antigens that promote the recruitment of macrophages, neutrophils, DC, and B cells, as well as the formation of autoantibodies in the pancreas [55]. These autoantibodies are usually directed against insulin, insulinoma-associated antigen (IA) 2, 65-kD isoform of glutamic acid decarboxylase (GAD-65), β-cell-specific zinc transporter (Znt8), and islet cell (ICA) 512, which are not only the major autoantibody targets but also the main epitopes activating autoreactive T cells [56]. Here DC pick up antigens and immune complexes by pinocytosis and, upon activation, migrate to the pancreatic lymph nodes to present β-cell antigens to an abnormal number of autoreactive T cells, which are there because of a defective immune tolerance. Then, autoreactive T cells become fully activated and home into the islets. It has to be noted that usually T cells can be activated by the recognition of autoantigens through MHC class II on antigen-presenting cells and/or through MHC class I on β-cells [57, 58]. Then, one way or the other, activated CD8+ T cells will destroy the β-cells by the release of cytolytic granules containing perforins and granzymes or by FasL-dependent interactions, while CD4+ release proinflammatory cytokines (Figure 2(a)). At the same time, inflammation and tissue damage are further worsened by an impairment of Treg cells, which seem to be either lacking [59] and/or defective [60] in T1DM. As for the natural history of the disease, this islet inflammation (or insulitis) generally precedes T1DM onset [61] and it corresponds to the stage where autoantibodies are detectable [62]. Of note, neither autoantibodies nor B cells seem to be critically involved in T1DM pathogenesis, as T1DM can affect patients with X-linked agammaglobulinemia [63]. Anyway, when 70–80% of β-cells have been destroyed, the residual insulin-producing cells are insufficient to maintain glucose tolerance and T1DM develops [64].

Bottom Line: TRAIL or tumor necrosis factor (TNF) related apoptosis-inducing ligand is a member of the TNF superfamily of proteins, whose best characterized function is the induction of apoptosis in tumor, infected, or transformed cells through activation of specific receptors.In nontransformed cells, however, the actions of TRAIL are less well characterized.Here we review TRAIL biological actions, its effects on the immune system, and how and to what extent it has been shown to protect against diabetes.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical, Surgical, and Health Sciences, University of Trieste, Cattinara University Hospital, Strada di Fiume 447, 34100 Trieste, Italy.

ABSTRACT
TRAIL or tumor necrosis factor (TNF) related apoptosis-inducing ligand is a member of the TNF superfamily of proteins, whose best characterized function is the induction of apoptosis in tumor, infected, or transformed cells through activation of specific receptors. In nontransformed cells, however, the actions of TRAIL are less well characterized. Recent studies suggest that TRAIL may be implicated in the development and progression of diabetes. Here we review TRAIL biological actions, its effects on the immune system, and how and to what extent it has been shown to protect against diabetes.

Show MeSH
Related in: MedlinePlus