NFAT1 deficit and NFAT2 deficit attenuate EAE via different mechanisms

Dietz, Lena; Frommer, Friederike; Vogel, Anna-Lena; Vaeth, Martin; Serfling, Edgar; Waisman, Ari; Buttmann, Mathias; Berberich‐Siebelt, Friederike

doi:10.1002/eji.201444638

Cited by 32 publications

(39 citation statements)

References 53 publications

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“…Hemizygous deletions of NFATC1 were found to be significantly correlated with degenerative lumbar scoliosis [Shin et al, ]. Additionally, NFATC1 hemizygosity may actually be protective against autoimmune disease [Dietz et al, ]. It is our observation that this group has more autoimmune disease that might be expected, and is therefore a current area of investigation.…”

Section: Gene Dosage Mapmentioning

confidence: 80%

Consequences of chromsome18q deletions

Cody

Sebold

Heard³

et al. 2015

American J of Med Genetics Pt C

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Providing clinically relevant prognoses and treatment information for people with a chromsome18q deletion is particularly challenging because every unrelated person has a unique region of hemizygosity. The hemizygous region can involve almost any region of 18q including between 1 and 101 genes (30 Mb of DNA). Most individuals have terminal deletions, but in our cohort of over 350 individuals 23% have interstitial deletions. Because of this heterogeneity, we take a gene by gene approach to understanding the clinical consequences. There are 196 genes on 18q. We classified 133 of them as dosage insensitive, 15 (8%) as dosage sensitive leading to haploinsufficiency while another 10 (5%) have effects that are conditionally haploinsufficient and are dependent on another factor, genetic or environmental in order to cause an abnormal phenotype. Thirty-seven genes (19%) have insufficient information to classify their dosage effect. Phenotypes attributed to single genes include: congenital heart disease, minor bone morphology changes, central nervous system dysmyelination, expressive speech delay, vesicouretreral reflux, polyposis, Pitt-Hopkins syndrome, intellectual disability, executive function impairment, male infertility, aural atresia, and high frequency sensorineural hearing loss. Additionally, identified critical regions for other phenotypes include: adolescent idiopathic scoliosis and pectus excavatum, Virchow-Robin perivascular spaces, small corpus callosum, strabismus, atopic disorders, mood disorder, IgA deficiency, nystagmus, congenital heart disease, kidney malformation, vertical talus, CNS dysmyelination growth hormone deficiency and cleft palate. Together these findings make it increasingly feasible to compile an individualized syndrome description based on each person's individuated genotype. Future work will focus on understanding molecular mechanisms leading to treatment.

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Section: Gene Dosage Mapmentioning

confidence: 80%

Consequences of chromsome18q deletions

Cody

Sebold

Heard³

et al. 2015

American J of Med Genetics Pt C

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“…Thus, BMDCs overexpressing Nr4a2 have a tolerogenic phenotype by virtue of which they are able to induce tolerance in the EAE mice model and prevent its development. Tolerogenic DCs regulate tolerance, in part, by promoting the expansion of Treg cells and/or attenuating T H 1/T H 17 responses that contribute to the pathogenesis of several inflammatory disorders, including EAE . To determine if Nr4a2‐induced tolerogenic DCs regulate the expansion of Treg cells, we isolated cells from spleen and looked at the percentage of Treg cells by analyzing the Foxp3 expression using FACS.…”

Section: Resultsmentioning

confidence: 99%

Nuclear receptor expression atlas in BMDCs: Nr4a2 restricts immunogenicity of BMDCs and impedes EAE

2016

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The nuclear receptor (NR) superfamily of transcription factors regulates various key aspects of physiological processes; however, their role(s) in immune cells' function are just beginning to unravel. Although few NRs have been shown to be critical for dendritic cell (DC) function, a lack of knowledge about their complete representation in DCs has limited the ability to harness their full potential. Here, we performed a comprehensive NR expression profiling and identified the key members of NR superfamily being expressed in immature, immunogenic, and tolerogenic DCs. Comparative analysis revealed discrete changes in the expression of various NRs among the studied DC subtypes, indicating a likely role in the modulation of DC functionality. Next, we characterized Nr4a2, a member of orphan NR family, and found that it suppresses the activation of bone marrow derived dendritic cells triggered by LPS. Overexpression and knockdown of Nr4a2 demonstrated that Nr4a2 orchestrates the expression of immunoregulatory genes, hence inducing a tolerogenic phenotype in bone marrow derived dendritic cells. Furthermore, we also found that Nr4a2 provides protection from EAE by promoting an increase in Treg cells, while limiting effector T cells. Our findings suggest a previously unidentified role for Nr4a2 as a regulator of DC tolerogenicity and demonstrate its potential as therapeutic target in DC-associated pathophysiologies. Keywords: Dendritic cells EAE Immune tolerance Nr4a2 Nuclear receptors Treg cellsAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionDendritic cells (DCs) are indispensable immune sentinels that bridge the innate and adaptive immune responses. They have been primarily looked upon as inducers of immunity-immunogenic DCs; however, there is a growing body of evidence to support another facet of their function in induction and maintenance of tolerance-tolerogenic DCs. The phenotypic characteristics distinguishing these two functional DC phenotypes, immunogenic or tolerogenic, have begun to unravel. [1,9]. Interestingly, many of these modulators are known to be able to exert their effects through the members of nuclear receptor (NR) superfamily, which comprises 49 members in mice and 48 in humans.The NR superfamily comprises ligand-sensitive transcription factors that regulate various metabolic, developmental, homeostatic, and other physiological processes by modulating the expression of target genes [10,11]. NRs have been classified into three categories depending upon the nature of their ligands: (i) endocrine NRs that mediate the effects of endocrine hormones, (ii) orphan NRs whose regulatory ligands have not yet been identified, and (iii) adopted orphan NRs that were originally identified as orphan NRs, but were subsequently found to bind dietary lipids as their ligands [12,13]. Unlike other transcription factors, NRs are exceptionally promising therapeutic targets in biomedicine, because of their druggable potential. Consequently, NRs ...

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“…Moreover, NFAT1 hyperactivation decreased experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein (MOG), a key regulator of CNS myelination [175, 176]. …”

Section: Nervous System Functionmentioning

confidence: 99%

The Emerging Roles of the Calcineurin-Nuclear Factor of Activated T-Lymphocytes Pathway in Nervous System Functions and Diseases

Kipanyula

Kimaro

Etet

2016

Journal of Aging Research

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The ongoing epidemics of metabolic diseases and increase in the older population have increased the incidences of neurodegenerative diseases. Evidence from murine and cell line models has implicated calcineurin-nuclear factor of activated T-lymphocytes (NFAT) signaling pathway, a Ca2+/calmodulin-dependent major proinflammatory pathway, in the pathogenesis of these diseases. Neurotoxins such as amyloid-β, tau protein, and α-synuclein trigger abnormal calcineurin/NFAT signaling activities. Additionally increased activities of endogenous regulators of calcineurin like plasma membrane Ca2+-ATPase (PMCA) and regulator of calcineurin 1 (RCAN1) also cause neuronal and glial loss and related functional alterations, in neurodegenerative diseases, psychotic disorders, epilepsy, and traumatic brain and spinal cord injuries. Treatment with calcineurin/NFAT inhibitors induces some degree of neuroprotection and decreased reactive gliosis in the central and peripheral nervous system. In this paper, we summarize and discuss the current understanding of the roles of calcineurin/NFAT signaling in physiology and pathologies of the adult and developing nervous system, with an emphasis on recent reports and cutting-edge findings. Calcineurin/NFAT signaling is known for its critical roles in the developing and adult nervous system. Its role in physiological and pathological processes is still controversial. However, available data suggest that its beneficial and detrimental effects are context-dependent. In view of recent reports calcineurin/NFAT signaling is likely to serve as a potential therapeutic target for neurodegenerative diseases and conditions. This review further highlights the need to characterize better all factors determining the outcome of calcineurin/NFAT signaling in diseases and the downstream targets mediating the beneficial and detrimental effects.

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NFAT1 deficit and NFAT2 deficit attenuate EAE via different mechanisms

Cited by 32 publications

References 53 publications

Consequences of chromsome18q deletions

Consequences of chromsome18q deletions

Nuclear receptor expression atlas in BMDCs: Nr4a2 restricts immunogenicity of BMDCs and impedes EAE

The Emerging Roles of the Calcineurin-Nuclear Factor of Activated T-Lymphocytes Pathway in Nervous System Functions and Diseases

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