Macrophage IFN-I signaling promotes autoreactive T cell infiltration into islets in type 1 diabetes model

Marro, Brett S.; Legrain, Sarah; Ware, Brian C.; Oldstone, Michael B. A.

doi:10.1172/jci.insight.125067

Cited by 33 publications

(24 citation statements)

References 50 publications

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“…Studies have found that macrophages are crucial for the development of diabetes in both the NOD mouse (21,22) and the RIP-LCMV-GP mouse (23). We also found that when we depleted macrophages using clodronate liposomes in the RIP-LCMV-GP model, the mice were protected from the development of diabetes (Fig.…”

Section: Macrophages Are Required For the Onset Of T1d And Respond Tosupporting

confidence: 62%

Interference with pancreatic sympathetic signaling halts the onset of diabetes in mice

2020

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The notably lobular distribution of immune lesions in type 1 diabetes (T1D) has been hypothesized to be the result of innervation within the pancreas. To investigate whether neuroimmune interactions could explain this phenomenon, we explored the impact of sympathetic signaling in the RIP-LCMV-GP mouse model of autoimmune diabetes. In this model, the CD8+ T cell attack on β cells replicates a key pathogenic feature of human T1D. We found that inhibition of α1 adrenoceptors, ablation of sympathetic nerves, and surgical denervation all had a protective effect in this model, without affecting the systemic presence of β cell–reactive CD8+ T cells. In vivo multiphoton imaging revealed a local effect within pancreatic islets including limited infiltration of both macrophages and β cell–specific CD8+ T cells. Islet-resident macrophages expressed adrenoceptors and were responsive to catecholamines. Islet macrophages may therefore constitute a pivotal neuroimmune signaling relay and could be a target for future interventions in T1D.

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Section: Macrophages Are Required For the Onset Of T1d And Respond Tosupporting

confidence: 62%

Interference with pancreatic sympathetic signaling halts the onset of diabetes in mice

2020

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“…Similarly, no differences were observed in apparent cell proliferation rates in the SVF between control and iAdFASNKO mice, as detected by labeling the SVF cells Clodronate liposomes were previously shown to selectively target and deplete phagocytic cells of the mononuclear phagocyte system (effectively monocytes/macrophages) [59][60][61][62] . This approach for adipose tissue macrophage depletion has been used successfully before by others [63][64][65] .…”

mentioning

confidence: 90%

Single Cell RNA Profiling Reveals Adipocyte to Macrophage Signaling Sufficient to Enhance Thermogenesis

Henriques

Bedard

Guilherme

et al. 2020

Preprint

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The "browning" of inguinal white adipose tissue (iWAT) through increased abundance of thermogenic beige/brite adipocytes is induced by cold exposure and many other perturbations in association with beneficial systemic metabolic effects.Adipose browning is reported to require activation of sympathetic nerve fibers (SNF), aided by alternately activated macrophages within iWAT. Here we demonstrate the first example of a non-cell autonomous pathway for iWAT browning that is fully independent of SNF activity. Thus, the strong induction of thermogenic adipocytes prompted by deletion of adipocyte fatty acid synthase (iAdFASNKO mice) was unaffected by denervation or the deletion of SNF modulator Neuregulin-4. However, browning of iWAT in iAdFASNKO mice does require adipocyte cAMP/protein kinase A signaling, as it was blocked in adipocyteselective Fasn/Gsa double KO mice. Single-cell transcriptomic analysis of iAdFASNKO mouse adipose stromal cells revealed increased macrophages displaying gene expression signatures of the alternately activated type.Mechanistically, depletion of such phagocytic immune cells in iAdFASNKO mice fully abrogated appearance of thermogenic adipocytes in iWAT. Altogether, these findings reveal an unexpected pathway of cAMP/PKA-dependent iWAT browning that is initiated by adipocyte signals and caused by macrophage-like cells independent of sympathetic neuron involvement.

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“…Studies investigating the role of IFN-α/β in initiating T1D in NOD mice found that NOD mice have an IFN-α gene signature prior to T1D onset similar to human T1D patients [127]. Additionally, suppressing IFN signaling through neutralizing antibodies to the interferon-alpha and -beta receptor subunit 1 (IFNAR1) was effective in significantly delaying T1D onset [127,128]. Paralleling the neutralization of IFNAR1 to delay T1D progression, IFNAR1 KO mice also have a significant delay in T1D development [129,130].…”

Section: Type I Interferons In T1dmentioning

confidence: 99%

“…Chemokine synthesis leads to the recruitment of APCs, which upregulate MHC-II. APCs generate IL-6, tumor necrosis factor (TNF), and ROS [ 164 ] as an antiviral response, while concomitantly regulating T cell entry into islets allowing for β-cell destruction [ 128 , 165 , 166 ] ( Figure 1 B). APCs promote the activation of CD4 to produce IFN-γ and ROS to augment antiviral responses.…”

Section: Immune Cell Response To Viral Infections In T1dmentioning

confidence: 99%

Innate Viral Sensor MDA5 and Coxsackievirus Interplay in Type 1 Diabetes Development

Blum¹,

Tse²

2020

Microorganisms

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Type 1 diabetes (T1D) is a polygenic autoimmune disease characterized by immune-mediated destruction of insulin-producing β-cells. The concordance rate for T1D in monozygotic twins is ≈30–50%, indicating that environmental factors also play a role in T1D development. Previous studies have demonstrated that enterovirus infections such as coxsackievirus type B (CVB) are associated with triggering T1D. Prior to autoantibody development in T1D, viral RNA and antibodies against CVB can be detected within the blood, stool, and pancreata. An innate pathogen recognition receptor, melanoma differentiation-associated protein 5 (MDA5), which is encoded by the IFIH1 gene, has been associated with T1D onset. It is unclear how single nucleotide polymorphisms in IFIH1 alter the structure and function of MDA5 that may lead to exacerbated antiviral responses contributing to increased T1D-susceptibility. Binding of viral dsRNA via MDA5 induces synthesis of antiviral proteins such as interferon-alpha and -beta (IFN-α/β). Viral infection and subsequent IFN-α/β synthesis can lead to ER stress within insulin-producing β-cells causing neo-epitope generation, activation of β-cell-specific autoreactive T cells, and β-cell destruction. Therefore, an interplay between genetics, enteroviral infections, and antiviral responses may be critical for T1D development.

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Macrophage IFN-I signaling promotes autoreactive T cell infiltration into islets in type 1 diabetes model

Cited by 33 publications

References 50 publications

Interference with pancreatic sympathetic signaling halts the onset of diabetes in mice

Interference with pancreatic sympathetic signaling halts the onset of diabetes in mice

Single Cell RNA Profiling Reveals Adipocyte to Macrophage Signaling Sufficient to Enhance Thermogenesis

Innate Viral Sensor MDA5 and Coxsackievirus Interplay in Type 1 Diabetes Development

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