Janus-like opposing roles of CD47 in autoimmune brain inflammation in
                    humans and mice

Han, May; Lundgren, Deborah H.; Jaiswal, Siddhartha; Chao, Mark; Graham, Kareem; Garris, Christopher; Axtell, Robert C.; Ho, Peggy P.; Lock, Christopher; Woodard, Joslyn I.; Brownell, Sara E.; Zoudilova, Maria; Hunt, Jack F.V.; Baranzini, Sergio E.; Butcher, Eugene C.; Raine, Cedric S.; Sobel, Raymond A.; Han, David K.; Weissman, Irving L.; Steinman, Lawrence

doi:10.1084/jem.20101974

Cited by 142 publications

(131 citation statements)

References 31 publications

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“…6G). Moreover, gene expression analysis derived from the Gene Expression Omnibus database (GSE38010) (42) indicated the persistent upregulated expression of TFL over control samples from the histologically characterized acute to chronic plaques through chronic active plaques of multiple sclerosis brains, whereas the expression of Zc3h12a was lower than that in the control (Fig. 6H).…”

Section: Resolution Of Eae By Tfl Through Mrna Decay Of Il-17amentioning

confidence: 98%

Posttranscriptional Modulation of Cytokine Production in T Cells for the Regulation of Excessive Inflammation by TFL

Minagawa

Wakahashi

Kawano

et al. 2014

The Journal of Immunology

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Posttranscriptional machinery regulates inflammation and is associated with autoimmunity as well as tumorigenesis in collaboration with transcription factors. We previously identified the tumor suppressor gene transformed follicular lymphoma (TFL) on 6q25 in a patient with follicular lymphoma, which transformed into diffuse large B cell lymphoma. TFL families have a common RNase domain that governs macrophage-mediated inflammation. In human peripheral blood, TFL is dominantly expressed at the glycine- and tryptophan-rich cytoplasmic processing bodies of T lymphocytes, and it is persistently upregulated in activated T cells. To address its physiological role, we established TFL−/− mice in which TFL−/− lymphocytes proliferated more rapidly than TFL+/+ upon stimulation with inappropriate cytokine secretion, including IL-2, IL-6, and IL-10. Moreover, TFL inhibited the synthesis of cytokines such as IL-2, IL-6, IL-10, TNF-α, and IL-17a by 3′ untranslated region RNA degradation. Experimental autoimmune encephalitis induced in TFL−/− mice demonstrated persistent severe paralysis. CNS-infiltrated CD4+ T cells in TFL−/− mice contained a higher proportion of Th17 cells than did those in TFL+/+ mice during the resolution phase, and IL-17a mRNA levels were markedly increased in TFL−/− cells. These results suggest that TFL may play an important role in attenuating local inflammation by suppressing the infiltration of Th17 cells in the CNS during the resolution phase of experimental autoimmune encephalitis. TFL is a novel gradual and persistent posttranscriptional regulator, and the TFL-driven attenuation of excessive inflammation could contribute to recovery from T cell–mediated autoimmune diseases.

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Section: Resolution Of Eae By Tfl Through Mrna Decay Of Il-17amentioning

confidence: 98%

Posttranscriptional Modulation of Cytokine Production in T Cells for the Regulation of Excessive Inflammation by TFL

Minagawa

Wakahashi

Kawano

et al. 2014

The Journal of Immunology

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“…Mutant mice lacking the SIRPa cytoplasmic signaling domain were resistant to myelin oligodendrocyte glycoprotein-induced EAE and displayed reduced DC stimulation of myelin oligodendrocyte glycoprotein-dependent T cell proliferation (24). Similarly, CD47 2/2 mice were also EAE resistant due to impaired T cell responses (42). These observations highlight role of SIRPa-CD47 signaling in regulating DC function and T cell activation (43).…”

Section: Cd8amentioning

confidence: 98%

Polymorphism in the Innate Immune Receptor SIRPα Controls CD47 Binding and Autoimmunity in the Nonobese Diabetic Mouse

Wong

Mortin-Toth

Sung

et al. 2014

The Journal of Immunology

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The signal regulatory protein (SIRP) locus encodes a family of paired receptors that mediate both activating and inhibitory signals and is associated with type 1 diabetes (T1D) risk. The NOD mouse model recapitulates multiple features of human T1D and enables mechanistic analysis of the impact of genetic variations on disease. In this study, we identify Sirpa encoding an inhibitory receptor on myeloid cells as a gene in the insulin-dependent diabetes locus 13.2 (Idd13.2) that drives islet inflammation and T1D. Compared to T1D-resistant strains, the NOD variant of SIRPα displayed greater binding to its ligand CD47, as well as enhanced T cell proliferation and diabetogenic potency. Myeloid cell–restricted expression of a Sirpa transgene accelerated disease in a dose-dependent manner and displayed genetic and functional interaction with the Idd5 locus to potentiate insulitis progression. Our study demonstrates that variations in both SIRPα sequence and expression level modulate T1D immunopathogenesis. Thus, we identify Sirpa as a T1D risk gene and provide insight into the complex mechanisms by which disease-associated variants act in concert to drive defined stages in disease progression.

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“…Fcγ receptor (FcγR) activation stimulates the association between SHP-1 and SIRPα, which in turn inhibits FcγR-and complement receptor-mediated phagocytosis (75,78). CD47 expression is downregulated in MS brain lesions (79). Although CD47-deficient mice are resistant to EAE, primarily owing to lack of APC activation, blocking CD47 enhances disease progression by increasing myelin phagocytosis in the CNS (79).…”

Section: Immune Cells Involved In Neurodegenerationmentioning

confidence: 99%

CNS inflammation and neurodegeneration

Chitnis¹,

Weiner²

2017

Journal of Clinical Investigation

398

240

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Janus-like opposing roles of CD47 in autoimmune brain inflammation in humans and mice

Abstract: CD47 exerts different effects on disease in distinct cell types and locations and during different stages of experimental autoimmune encephalomyelitis.

Cited by 142 publications

References 31 publications

Posttranscriptional Modulation of Cytokine Production in T Cells for the Regulation of Excessive Inflammation by TFL

Posttranscriptional Modulation of Cytokine Production in T Cells for the Regulation of Excessive Inflammation by TFL

Polymorphism in the Innate Immune Receptor SIRPα Controls CD47 Binding and Autoimmunity in the Nonobese Diabetic Mouse

CNS inflammation and neurodegeneration

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