CXCR3, CXCR5, CXCR6, and CXCR7 in Diabetes

Fallahi, Poupak; Corrado, Alda; Domenicantonio, Andrea Di; Frenzilli, Giada; Antonelli, Alessandro; Ferrari, Silvia

doi:10.2174/1389450115666141229153949

Cited by 13 publications

(15 citation statements)

References 73 publications

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“…Scavenger chemokine (CXC motif) receptor 7 (CXCR7) is a direct target of HIC1 [ 27 ]. CXCR7 and other chemokine receptors are suggested to be T1D determinants, especially in autoimmunity and beta cell destruction [ 28 ]. HIC1 has also been demonstrated to modulate transcriptional stimulation of the genes regulated by canonical Wnt/beta-catenin signaling [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Coxsackievirus-Induced Proteomic Alterations in Primary Human Islets Provide Insights for the Etiology of Diabetes

Nyalwidhe

Gallagher

Glenn

et al. 2017

Journal of the Endocrine Society

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Enteroviral infections have been associated with the development of type 1 diabetes (T1D), a chronic inflammatory disease characterized by autoimmune destruction of insulin-producing pancreatic beta cells. Cultured human islets, including the insulin-producing beta cells, can be infected with coxsackievirus B4 (CVB4) and thus are useful for understanding cellular responses to infection. We performed quantitative mass spectrometry analysis on cultured primary human islets infected with CVB4 to identify molecules and pathways altered upon infection. Corresponding uninfected controls were included in the study for comparative protein expression analyses. Proteins were significantly and differentially regulated in human islets challenged with virus compared with their uninfected counterparts. Complementary analyses of gene transcripts in CVB4-infected primary islets over a time course validated the induction of RNA transcripts for many of the proteins that were increased in the proteomics studies. Notably, infection with CVB4 results in a considerable decrease in insulin. Genes/proteins modulated during CVB4 infection also include those involved in activation of immune responses, including type I interferon pathways linked to T1D pathogenesis and with antiviral, cell repair, and inflammatory properties. Our study applies proteomics analyses to cultured human islets challenged with virus and identifies target proteins that could be useful in T1D interventions.

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Section: Discussionmentioning

confidence: 99%

Coxsackievirus-Induced Proteomic Alterations in Primary Human Islets Provide Insights for the Etiology of Diabetes

Nyalwidhe

Gallagher

Glenn

et al. 2017

Journal of the Endocrine Society

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“…Between mice and humans, more than half the chemokine ligands and receptors have been implicated to have a role in T1D [55] (Table 2). Many of the chemokines produced within the islets are IFN-stimulated genes driven by IFN-γ [4,14,[55][56][57][58][59][60]. Our laboratory and others have shown that chemokine receptor signaling on T cells is necessary for T cell recruitment to previously infiltrated islets [13,15].…”

Section: Role Of Chemokines In Leukocyte Trafficking To the Isletsmentioning

confidence: 91%

“…Unfortunately, while targeting of individual chemokine pathways has been effective at delaying trafficking to uninfiltrated islets, it does not seem to be effective in inhibiting trafficking once infiltration is established [13,57,[64][65][66]. This is due probably to the fact that chemokines are highly redundant and promiscuous, being able to bind multiple chemokine receptors on a variety of cell types [4,14,[55][56][57][58][59][60].…”

Section: Role Of Chemokines In Leukocyte Trafficking To the Isletsmentioning

confidence: 99%

Immune cell trafficking to the islets during type 1 diabetes

Sandor

Jacobelli

Friedman

2019

Clinical and Experimental Immunology

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Inhibition of immune cell trafficking to the pancreatic islets during type 1 diabetes (T1D) has therapeutic potential, since targeting of T cell and B cell trafficking has been clinically effective in other autoimmune diseases.Trafficking to the islets is characterized by redundancy in adhesion molecule and chemokine usage, which has not enabled effective targeting to date. Additionally, cognate antigen is not consistently required for T cell entry into the islets throughout the progression of disease. However, myeloid cells are required to enable T cell and B cell entry into the islets, and may serve as a convergence point in the pathways controlling this process. In this review we describe current knowledge of the factors that mediate immune cell trafficking to pancreatic islets during T1D progression.

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“…Downstream of this response, numerous proinflammatory cytokines and chemokines have been detected in patients with diabetes ( 33 , 34 ). One of these, IFN-gamma (IFN-γ), has been shown to play an important, albeit controversial, role in T1D pathogenesis ( 7 , 35 ).…”

Section: Indirect Evidence For Virus Infections In T1dmentioning

confidence: 99%

The Four-Way Stop Sign: Viruses, 12-Lipoxygenase, Islets, and Natural Killer Cells in Type 1 Diabetes Progression

2017

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Natural killer (NK) cells represent an important effector arm against viral infection, and mounting evidence suggests that viral infection plays a role in the development of type 1 diabetes (T1D) in at least a portion of patients. NK cells recognize their target cells through a delicate balance of inhibitory and stimulatory receptors on their surface. If unbalanced, NK cells have great potential to wreak havoc in the pancreas due to the beta cell expression of the as-yet-defined NKp46 ligand through interactions with the activating NKp46 receptor found on the surface of most NK cells. Blocking interactions between NKp46 and its ligand protects mice from STZ-induced diabetes, but differential expression non-diabetic and diabetic donor samples have not been tested. Additional studies have shown that peripheral blood NK cells from human T1D patients have altered phenotypes that reduce the lytic and functional ability of the NK cells. Investigations of humanT1D pancreas tissues have indicated that the presence of NK cells may be beneficial despite their infrequent detection. In non-obese diabetic (NOD) mice, we have noted that NK cells express high levels of the proinflammatory mediator 12/15-lipoxygenase (12/15-LO), and decreased levels of stimulatory receptors. Conversely, NK cells of 12/15-LO deficient NOD mice, which are protected from diabetes development, express significantly higher levels of stimulatory receptors. Furthermore, the human NK92 cell line expresses the ALOX12 protein [human 12-lipoxygenase (12-LO), related to mouse 12/15-LO] via Western blotting. Human 12-LO is upregulated in the pancreas of both T1D and T2D human donors with insulin-containing islets, showing a link between 12-LO expression and diabetes progression. Therefore, our hypothesis is that NK cells in those susceptible to developing T1D are unable to function properly during viral infections of pancreatic beta cells due to increased 12-LO expression and activation, which contributes to increased interferon-gamma production and an imbalance in activating and inhibitory NK cell receptors, and may contribute to downstream autoimmune T cell responses. The work presented here outlines evidence from our lab, as well as published literature, supporting our hypothesis, including novel data.

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CXCR3, CXCR5, CXCR6, and CXCR7 in Diabetes

Cited by 13 publications

References 73 publications

Coxsackievirus-Induced Proteomic Alterations in Primary Human Islets Provide Insights for the Etiology of Diabetes

Coxsackievirus-Induced Proteomic Alterations in Primary Human Islets Provide Insights for the Etiology of Diabetes

Immune cell trafficking to the islets during type 1 diabetes

The Four-Way Stop Sign: Viruses, 12-Lipoxygenase, Islets, and Natural Killer Cells in Type 1 Diabetes Progression

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