scholarly journals TGF-β inhibitor Smad7 regulates dendritic cell-induced autoimmunity

2017 ◽  
Vol 114 (8) ◽  
pp. E1480-E1489 ◽  
Author(s):  
Dominika Lukas ◽  
Nir Yogev ◽  
Junda M. Kel ◽  
Tommy Regen ◽  
Ilgiz A. Mufazalov ◽  
...  
Keyword(s):  
T Cells ◽  
Tolerance Induction ◽  
Autoimmune Encephalomyelitis ◽  
Elevated Expression ◽  
The Central Nervous System ◽  
Smad7 Expression ◽  
Ifn Γ ◽  
Tolerogenic Function ◽  
Anti Inflammatory Cytokine ◽  
Experimental Autoimmune

TGF-β is an anti-inflammatory cytokine whose signaling is negatively controlled by Smad7. Previously, we established a role for Smad7 in the generation of autoreactive T cells; however, the function of Smad7 in dendritic cells (DCs) remains elusive. Here, we demonstrate that DC-specific Smad7 deficiency resulted in elevated expression of the transcription factors Batf3 and IRF8, leading to increased frequencies of CD8+CD103+DCs in the spleen. Furthermore, Smad7-deficient DCs expressed higher levels of indoleamine 2,3-dioxygenase (IDO), an enzyme associated with tolerance induction. Mice devoid of Smad7 specifically in DCs are resistant to the development of experimental autoimmune encephalomyelitis (EAE) as a result of an increase of protective regulatory T cells (Tregs) and reduction of encephalitogenic effector T cells in the central nervous system. In agreement, inhibition of IDO activity or depletion of Tregs restored disease susceptibility. Intriguingly, when Smad7-deficient DCs also lacked the IFN-γ receptor, the mice regained susceptibility to EAE, demonstrating that IFN-γ signaling in DCs mediates their tolerogenic function. Our data indicate that Smad7 expression governs splenic DC subset differentiation and is critical for the promotion of their efficient function in immunity.

scholarly journals Regional CNS responses to IFN-γ determine lesion localization patterns during EAE pathogenesis

2008 ◽  
Vol 205 (11) ◽  
pp. 2633-2642 ◽  
Author(s):  
Jason R. Lees ◽  
Paul T. Golumbek ◽  
Julia Sim ◽  
Denise Dorsey ◽  
John H. Russell
Keyword(s):  
Spinal Cord ◽  
T Cells ◽  
Brain Stem ◽  
Clinical Outcomes ◽  
Clinical Symptoms ◽  
Inflammatory Cells ◽  
Th1 Cells ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Ifn Γ

The localization of inflammatory foci within the cerebellum is correlated to severe clinical outcomes in multiple sclerosis (MS). Previous studies of experimental autoimmune encephalomyelitis (EAE), a model of MS, revealed distinct clinical outcomes correlated with the capacity of the animal to produce IFN-γ. Outcomes were linked to localization of inflammatory cells in either the spinal cord (wild type [WT]) or the cerebellum and brain stem (IFN-γ deficient). We demonstrate, using an adoptive transfer system, that the ability of the central nervous system (CNS) to sense pathogenic T cell–produced IFN-γ during EAE initiation determines the sites of CNS pathogenesis. Transfer of WT Th1 cells into IFN-γ receptor–deficient mice results in pathogenic invasion of the brain stem and cerebellum with attendant clinical symptoms, which are identical to the disease observed after transfer of IFN-γ–deficient T cells to WT hosts. Inflammation of the spinal cord associated with classical EAE is abrogated in both IFN-γ–deficient systems. Cotransfer of CNS antigen-specific WT Th1 cells with IFN-γ–deficient T cells is sufficient to restore spinal cord invasion and block cerebellar and brain stem invasion. These data demonstrate that interaction between IFN-γ and host CNS cells during the initiation of EAE can selectively promote or suppress neuroinflammation and pathogenesis.

scholarly journals TGF-β in Mice Ameliorates Experimental Autoimmune Encephalomyelitis in Regulating NK Cell Activity

2019 ◽  
Vol 28 (9-10) ◽  
pp. 1155-1160 ◽  
Author(s):  
J. Xu ◽  
Y. Wang ◽  
H. Jiang ◽  
M. Sun ◽  
J. Gao ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Nk Cells ◽  
Nk Cell ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Experimental Autoimmune

Multiple sclerosis is a disease characterized by inflammation and demyelination located in the central nervous system. Experimental autoimmune encephalomyelitis (EAE) is the most common animal model for multiple sclerosis (MS). Although the roles of T cells in MS/EAE have been well investigated, little is known about the functions of other immune cells in the neuroinflammation model. Here we found that an essential cytokine transforming growth factor β (TGF-β) which could mediate the differentiation of Th17/regulatory T cells was implicated in the natural killer (NK) cells’ activity in EAE. In EAE mice, TGF-β expression was first increased at the onset and then decreased at the peak, but the expressions of TGF-β receptors and downstream molecules were not affected in EAE. When we immunized the mice with MOG antigen, it was revealed that TGF-β treatment reduced susceptibility to EAE with a lower clinical score than the control mice without TGF-β. Consistently, inflammatory cytokine production was reduced in the TGF-β treated group, especially with downregulated pathogenic interleukin-17 in the central nervous system tissue. Furthermore, TGF-β could increase the transcription level of NK cell marker NCR1 both in the spleen and in the CNS without changing other T cell markers. Meanwhile TGF-β promoted the proliferation of NK cell proliferation. Taken together, our data demonstrated that TGF-β could confer protection against EAE model in mice through NK cells, which would be useful for the clinical therapy of MS.

Myeloid cells: The Trojan horse for T cell invasion into the brain

2019 ◽  
Vol 11 (520) ◽  
pp. eaaz9757
Author(s):  
Gilbert Gallardo
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
Cell Invasion ◽  
Myeloid Cells ◽  
Autoimmune Encephalomyelitis ◽  
Lectin Receptors ◽  
The Central Nervous System ◽  
The Brain ◽  
Experimental Autoimmune

C-type lectin receptors on myeloid cells regulate the activation and infiltration of T cells into the central nervous system in experimental autoimmune encephalomyelitis.

scholarly journals Aspirin ameliorates experimental autoimmune encephalomyelitis through interleukin-11–mediated protection of regulatory T cells

2018 ◽  
Vol 11 (558) ◽  
pp. eaar8278 ◽  
Author(s):  
Susanta Mondal ◽  
Malabendu Jana ◽  
Sridevi Dasarathi ◽  
Avik Roy ◽  
Kalipada Pahan
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Clinical Symptoms ◽  
Interleukin 4 ◽  
T Helper 17 ◽  
Autoimmune Encephalomyelitis ◽  
Relapsing Remitting ◽  
The Central Nervous System ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is a human disease that results from autoimmune T cells targeting myelin protein that is expressed within the central nervous system. In MS, the number of FoxP3-expressing regulatory T cells (Tregs) is reduced, which facilitates the activation of autoreactive T cells. Because aspirin (acetylsalicylic acid) is the most widely used nonsteroidal anti-inflammatory drug, we examined its immunomodulatory effect in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We found that low-dose aspirin suppressed the clinical symptoms of EAE in mouse models of both relapsing-remitting and chronic disease. Aspirin reduced the development of EAE driven by myelin basic protein (MBP)–specific T cells and the associated perivascular cuffing, inflammation, and demyelination. The effects of aspirin required the presence of CD25+FoxP3+ Tregs. Aspirin increased the amounts of Foxp3 and interleukin-4 (IL-4) in T cells and suppressed the differentiation of naïve T cells into T helper 17 (TH17) and TH1 cells. Aspirin also increased the transcription of Il11 mediated by the transcription factor CREB, which was necessary for the generation of Tregs. Neutralization of IL-11 negated the effects of aspirin on Treg development and exacerbated EAE. Furthermore, we found that IL-11 alone was sufficient to maintain the percentage of FoxP3+ Tregs and protect mice from EAE. These results identify a previously uncharacterized mode of action of aspirin.

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