Loss of Trex1 in Dendritic Cells Is Sufficient To Trigger Systemic Autoimmunity

Peschke, Katrin; Achleitner, Martin; Frenzel, Kathrin; Gerbaulet, Alexander; Ada, Servi Remzi; Zeller, Nicolas; Lienenklaus, Stefan; Lesche, Mathias; Poulet, Claire; Naumann, Ronald; Dahl, Andreas; Ravens, Ursula; Günther, Claudia; Müller, Werner; Knobeloch, Klaus–Peter; Prinz, Marco; Roers, Axel; Behrendt, Rayk

doi:10.4049/jimmunol.1600722

Cited by 64 publications

(67 citation statements)

References 56 publications

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“…This approach revealed that loss of Trex1 in the entire hematopoietic system is sufficient to induce systemic autoimmunity (Peschke et al, 2016). …”

Section: Ifn-a Entry Into the Cns Might Be Facilitated By The Fact Thmentioning

confidence: 99%

“…However, in some cases, for example, of Aicardi-Goutières syndrome (AGS) the question arises as to whether the increased type I IFN activity identified in patients is a true pathological factor or an epiphenomenon. Further mouse models show that loss of TREX1 only in the hematopoietic system is sufficient to cause pathology (Peschke et al, 2016). The development of transgenic mice with astrocyte-targeted chronic overproduction of IFN-a showing neuropathologic features that mimic those found in AGS suggested a direct causal link between sustained high intrathecal IFN-a levels and the disease (Akwa et al, 1998;Campbell et al, 1999).…”

Section: T Ype I I Nt Er Fe R Onopath Ies With Impact On Cns F Unctionmentioning

confidence: 99%

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Type I interferon pathway in CNS homeostasis and neurological disorders

Blank

Prinz

2017

Glia

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117

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Type I interferons (IFNs), IFN-α and IFN-β, represent the major effector cytokines of the host immune response against viruses and other intracellular pathogens. These cytokines are produced via activation of numerous pattern recognition receptors, including the Toll-like receptor signaling network, retinoic acid-inducible gene-1 (RIG-1), melanoma differentiation-associated protein-5 (MDA-5) and interferon gamma-inducible protein-16 (IFI-16). Whilst the contribution of type I IFNs to peripheral immunity is well documented, they can also be produced by almost every cell in the central nervous system (CNS). Furthermore, IFNs can reach the CNS from the periphery to modulate the function of not only microglia and astrocytes, but also neurons and oligodendrocytes, with major consequences for cognition and behavior. Given the pleiotropic nature of type I IFNs, it is critical to determine their exact cellular impact. Inappropriate upregulation of type I IFN signaling and interferon-stimulated gene expression have been linked to several CNS diseases termed "interferonopathies" including Aicardi-Goutieres syndrome and ubiquitin specific peptidase 18 (USP18)-deficiency. In contrast, in the CNS of mice with virus-induced neuroinflammation, type I IFNs can limit production of other cytokines to prevent potential damage associated with chronic cytokine expression. This capacity of type I IFNs could also explain the therapeutic benefits of exogenous type I IFN in chronic CNS autoimmune diseases such as multiple sclerosis. In this review we will highlight the importance of a well-balanced level of type I IFNs for healthy brain physiology, and to what extent dysregulation of this cytokine system can result in brain 'interferonopathies'.

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“…This approach revealed that loss of Trex1 in the entire hematopoietic system is sufficient to induce systemic autoimmunity (Peschke et al, 2016). …”

Section: Ifn-a Entry Into the Cns Might Be Facilitated By The Fact Thmentioning

confidence: 99%

Section: T Ype I I Nt Er Fe R Onopath Ies With Impact On Cns F Unctionmentioning

confidence: 99%

Type I interferon pathway in CNS homeostasis and neurological disorders

Blank

Prinz

2017

Glia

Self Cite

117

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“…Interestingly, TREX1 is unable to degrade cytoplasmic DNA with the oxidized base 8-hydroxyguanosine (8-oxoG) [87], resulting in activation of an inflammatory response. Recent work has shown that deletion of Trex1 , specifically in the dendritic cells of mice, leads to development of systemic autoimmunity [88]. …”

Section: Mechanisms Associated With Defective Dna Repair and Slementioning

confidence: 99%

DNA repair and systemic lupus erythematosus

2017

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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with no known cure that affects at least five million people worldwide. Monozygotic twin concordance and familial aggregation studies strongly suggest that lupus results from genetic predisposition along with environmental exposures including UV light. The majority of the common risk alleles associated with genetic predisposition to SLE map to genes associated with the immune system. However, evidence is emerging that implicates a role for aberrant DNA repair in the development of lupus. Here we summarize our current knowledge of the potential association of lupus with mutations in DNA repair genes. We also discuss how defective or aberrant DNA repair could lead to the development of lupus.

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“…Of note, although Trex1 ‐deficient mice share the loss of function of TREX1 with patients with AGS1, these mice die prematurely from severe cardiac and non‐CNS‐related inflammation and fail to recapitulate the clinical features of human AGS (Morita et al, ; Stetson, Ko, Heidmann, & Medzhitov, ). Despite this major limitation, an IFN‐I gene signature and mild T cell infiltration is observed in the CNS of Trex1 ‐deficient mice (Peschke et al, ). Interestingly, the specific deletion of Trex1 in Cx3cr1 + microglia, but not in Nestin + astrocytes or neurons, results in elevated expression of IFN‐I stimulated genes and primary microglia from these mice exhibit spontaneous upregulation of IRGs.…”

Section: The Response Of Microglia In Il‐6‐ and Ifn‐i‐mediated Neuroimentioning

confidence: 99%

Microglia responses to interleukin‐6 and type I interferons in neuroinflammatory disease

West

Viengkhou

Campbell

et al. 2019

Glia

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Microglia are the resident macrophages of the central nervous system (CNS). They are a heterogenous, exquisitely responsive, and highly plastic cell population, which enables them to perform diverse roles. They sense and respond to the local production of many different signals, including an assorted range of cytokines. Microglia respond strongly to interleukin‐6 (IL‐6) and members of the type I interferon (IFN‐I) family, IFN‐alpha (IFN‐α), and IFN‐beta (IFN‐β). Although these cytokines are essential in maintaining homeostasis and for activating and regulating immune responses, their chronic production has been linked to the development of distinct human neurological diseases, termed “cerebral cytokinopathies.” IL‐6 and IFN‐α have been identified as key mediators in the pathogenesis of neuroinflammatory disorders including neuromyelitis optica and Aicardi‐Goutières syndrome, respectively, whereas IFN‐β has an emerging role as a causal factor in age‐associated cognitive decline. One of the key features that unites these diseases is the presence of highly reactive microglia. The current understanding is that microglia contribute to the development of cerebral cytokinopathies and represent an important therapeutic target. However, it remains to be resolved whether microglia have beneficial or detrimental effects. Here we review and discuss what is currently known about the microglial response to IL‐6 and IFN‐I, based on both animal models and clinical studies. Foundational knowledge regarding the microglial response to IL‐6 and IFN‐I is now being used to devise therapeutic strategies to ameliorate neuroinflammation and promote repair: either through targeting microglia, or by targeting the reduction of CNS levels or downstream biological pathways of IL‐6 or IFN‐I.

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Loss of Trex1 in Dendritic Cells Is Sufficient To Trigger Systemic Autoimmunity

Cited by 64 publications

References 56 publications

Type I interferon pathway in CNS homeostasis and neurological disorders

Type I interferon pathway in CNS homeostasis and neurological disorders

DNA repair and systemic lupus erythematosus

Microglia responses to interleukin‐6 and type I interferons in neuroinflammatory disease

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