scholarly journals NK-DC crosstalk controls the autopathogenic Th17 response through an innate IFN-γ–IL-27 axis

2015 ◽  
Vol 212 (10) ◽  
pp. 1739-1752 ◽  
Author(s):  
Wai Po Chong ◽  
Nicholas van Panhuys ◽  
Jun Chen ◽  
Phyllis B. Silver ◽  
Yingyos Jittayasothorn ◽  
...  
Keyword(s):  
Nk Cells ◽  
Feedback Loop ◽  
Dependent Manner ◽  
Autoimmune Encephalomyelitis ◽  
Th17 Response ◽  
Regulatory Circuit ◽  
Draining Lymph Node ◽  
Ifn Γ ◽  
Necessary And Sufficient ◽  
Experimental Autoimmune

IFN-γ is a pathogenic cytokine involved in inflammation. Paradoxically, its deficiency exacerbates experimental autoimmune encephalomyelitis, uveitis, and arthritis. Here, we demonstrate using IFN-γ−/− mice repleted with IFN-γ+/+ NK cells that innate production of IFN-γ from NK cells is necessary and sufficient to trigger an endogenous regulatory circuit that limits autoimmunity. After immunization, DCs recruited IFN-γ-producing NK cells to the draining lymph node and interacted with them in a CXCR3-dependent fashion. The interaction caused DCs to produce IL-27, which in turn enhanced IFN-γ production by NK cells, forming a self-amplifying positive feedback loop. IL-10, produced by the interacting cells themselves, was able to limit this process. The NK-DC–dependent IL-27 inhibited development of the adaptive pathogenic IL-17 response and induced IL-10–producing Tr1-like cells, which ameliorated disease in an IL-10-dependent manner. Our data reveal that an early NK-DC interaction controls the adaptive Th17 response and limits tissue-specific autoimmunity through an innate IFN-γ–IL-27 axis.

scholarly journals The neonatal microenvironment programs conventional and intestinal Tbet+γδT17 cells through the transcription factor STAT5

2019 ◽  
Author(s):  
Darshana Kadekar ◽  
Rasmus Agerholm ◽  
John Rizk ◽  
Heidi Neubauer ◽  
Tobias Suske ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cell Expansion ◽  
Dominant Role ◽  
Dependent Manner ◽  
Autoimmune Encephalomyelitis ◽  
Ifn Γ ◽  
Pass Through ◽  
Type 3 ◽  
First Time ◽  
Experimental Autoimmune

SummaryInterleukin(IL)-17-producing RORγt+γδ T (γδT17) cells develop in the embryonic thymus and participate in type 3 immune responses. Herein we show that γδT17 cells rapidly proliferate within neonatal lymph nodes and gut, where upon entry they uniquely upregulate Tbet and co-express IL-17, IL-22 and interferon(IFN) γ in a STAT3 and retinoic acid dependent manner. Neonatal expansion was halted in mice conditionally deficient in STAT5 and its loss resulted in γδT17 cell depletion from all adult organs. Hyperactive STAT5 mutant mice showed that the STAT5A homologue had a dominant role over STAT5B in promoting γδT17 cell expansion and downregulating gut-associated Tbet. In contrast, STAT5B preferentially expanded IFNγ-producing γδ populations. Importantly, mice lacking γδT17 cells due to STAT5 deficiency displayed a profound resistance to experimental autoimmune encephalomyelitis. Our data identify for the first time STAT5 as a key molecular checkpoint allowing γδT17 cells to pass through a critical neonatal developmental window to acquire tissue-specific characteristics essential for infection and autoimmunity.

scholarly journals Innate IFN-γ promotes development of experimental autoimmune encephalomyelitis: A role for NK cells and M1 macrophages

2014 ◽  
Vol 44 (10) ◽  
pp. 2903-2917 ◽  
Author(s):  
Lara S. Dungan ◽  
Niamh C. McGuinness ◽  
Louis Boon ◽  
Marina A. Lynch ◽  
Kingston H. G. Mills
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Nk Cells ◽  
Autoimmune Encephalomyelitis ◽  
M1 Macrophages ◽  
Ifn Γ ◽  
Experimental Autoimmune

scholarly journals Interleukin-6 Derived from the Central Nervous System May Influence the Pathogenesis of Experimental Autoimmune Encephalomyelitis in a Cell-Dependent Manner

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 330 ◽  
Author(s):  
Paula Sanchis ◽  
Olaya Fernández-Gayol ◽  
Gemma Comes ◽  
Anna Escrig ◽  
Mercedes Giralt ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Interleukin 6 ◽  
Critical Role ◽  
Cell Types ◽  
Minor Role ◽  
Dependent Manner ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

Background: Interleukin-6 (IL-6) is a pleiotropic and multifunctional cytokine that plays a critical role in induction of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS). Although EAE has always been considered a peripherally elicited disease, Il6 expression exclusively within central nervous system is sufficient to induce EAE development. Neurons, astrocytes, and microglia can secrete and respond to IL-6. Methods: To dissect the relevance of each cell source for establishing EAE, we generated and immunized conditional Il6 knockout mice for each of these cell types with myelin oligodendrocyte glycoprotein 35-55 (MOG35-55) peptide dissolved in complete Freund’s adjuvant (CFA) and supplemented with Mycobacterium tuberculosis. Results and conclusions: The combined results reveal a minor role for Il6 expression in both astrocytes and microglia for symptomatology and neuropathology of EAE, whereas neuronal Il6 expression was not relevant for the variables analyzed.

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.

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 A new mouse model to study restoration of interleukin-6 (IL-6) expression in a Cre-dependent manner: microglial IL-6 regulation of experimental autoimmune encephalomyelitis

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Paula Sanchis ◽  
Olaya Fernández-Gayol ◽  
Gemma Comes ◽  
Kevin Aguilar ◽  
Anna Escrig ◽  
...  
Keyword(s):  
Mouse Model ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Interleukin 6 ◽  
Clinical Symptoms ◽  
Recovery Of Function ◽  
Cell Types ◽  
Dependent Manner ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

Abstract Background Interleukin-6 (IL-6) is a pleiotropic cytokine that controls numerous physiological processes both in basal and neuroinflammatory conditions, including the inflammatory response to experimental autoimmune encephalomyelitis (EAE). IL-6 is produced by multiple peripheral and central cells, and until now, the putative roles of IL-6 from different cell types have been evaluated through conditional cell-specific IL-6 knockout mice. Nevertheless, these mice probably undergo compensatory responses of IL-6 from other cells, which makes it difficult to assess the role of each source of IL-6. Methods To give some insight into this problem, we have produced a novel mouse model: a conditional reversible IL-6 KO mouse (IL6-DIO-KO). By using double-inverted, open-reading-frame (DIO) technology, we created a mouse line with the loss of Il6 expression in all cells that can be restored by the action of Cre recombinase. Since microglia are one of the most important sources and targets of IL-6 into the central nervous system, we have recovered microglial Il6 expression in IL6-DIO-KO mice through breeding to Cx3cr1-CreER mice and subsequent injection of tamoxifen (TAM) when mice were 10–16 weeks old. Then, they were immunized with myelin oligodendrocyte glycoprotein 35-55 peptide (MOG35-55) 7 weeks after TAM treatment to induce EAE. Clinical symptoms and demyelination, CD3 infiltration, and gliosis in the spinal cord were evaluated. Results IL6-DIO-KO mice were resistant to EAE, validating the new model. Restoration of microglial Il6 was sufficient to develop a mild version of EAE-related clinical symptoms and neuropathology. Conclusions IL6-DIO-KO mouse is an excellent model to understand in detail the role of specific cellular sources of IL-6 within a recovery-of-function paradigm in EAE.

scholarly journals Alpinia oxyphylla Fruit Extract Ameliorates Experimental Autoimmune Encephalomyelitis through the Regulation of Th1/Th17 Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Kuo-Kuei Huang ◽  
Meng-Nan Lin ◽  
Yi-Ling Hsu ◽  
I-Huang Lu ◽  
I-Hong Pan ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Transcription Factor ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Quantitative Polymerase Chain Reaction ◽  
Histopathological Analysis ◽  
Autoimmune Encephalomyelitis ◽  
Th17 Response ◽  
Alpinia Oxyphylla ◽  
Experimental Autoimmune

Alpinia oxyphylla is a traditional Chinese medicine widely used for treating diarrhea, ulceration, and enuresis. Moreover, A. oxyphylla is effective for cognitive function improvement and nerve regeneration. Multiple sclerosis (MS) is a chronic neuronal inflammatory autoimmune disease that commonly affects young adults in high-latitude regions. The aim of this study was to evaluate the beneficial effects of A. oxyphylla in an experimental autoimmune encephalomyelitis (EAE) mouse model, which is an extensively used model for human MS. The ethanolic extract of A. oxyphylla fruit (AO-1) was orally administered to EAE mice. Our results showed AO-1 significantly reduced EAE symptoms. Histopathological analysis showed AO-1 reduced demyelination, inflammation, gliosis, and axonal swelling in the spinal cord. Furthermore, immunohistochemistry and quantitative polymerase chain reaction (qPCR) studies revealed that the infiltration of CD4+, CD8+ T cells, and CD11b+ monocytes into the spinal cord decreased in the AO-1-treated group. Mechanistically, the Th1 transcription factor T-bet, Th17 transcription factor retinoic acid receptor–related orphan receptor γ (RORγt), and inflammatory cytokines interferon (IFN)-γ and interleukin (IL)-17 were reduced in the spinal cords of mice treated with AO-1. The expression levels of T-bet and RORγt were also lowered in the spleens of those mice. Further in vitro study showed AO-1 inhibited production of IFN-γ, IL-2, and tumor necrosis factor-α from MOG35-55-peptide-stimulated splenocytes. One component isolated from AO-1, yakuchinone A, inhibited IL-17 production in vitro and reduced EAE symptoms in the mice. Collectively, our results indicate that AO-1 ameliorated the severity of EAE in mice and may involve the regulation of Th1/Th17 response. A. oxyphylla warrants further investigation, particularly regarding its clinical benefits for MS.

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