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 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 Chronic Toxoplasma gondii Infection Alleviates Experimental Autoimmune Encephalomyelitis by the Immune Regulation Inducing Reduction in IL-17A/Th17 Via Upregulation of SOCS3

2020 ◽  
Author(s):  
Do-Won Ham ◽  
Sang-Gyun Kim ◽  
Seung-Hwan Seo ◽  
Ji-Hun Shin ◽  
Sang Hyung Lee ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Immune Responses ◽  
Th17 Cells ◽  
Cell Activation ◽  
Dependent Manner ◽  
Autoimmune Encephalomyelitis ◽  
Socs3 Expression ◽  
Toxoplasma Gondii Infection ◽  
Experimental Autoimmune

AbstractExperimental autoimmune encephalomyelitis (EAE) is a mouse model of multiple sclerosis (MS), a demyelinating autoimmune disease caused by the infiltration of a harmful autoreactive Th1 and Th17 cells. To mitigate MS, which is impossible to cure with medication only, immunomodulatory interventions that prevent Th17 cell activation are ideal. The objective of the present study was to analyze the effect of Toxoplasma gondii infection on the onset of EAE. Our results found that Toxoplasma gondii infection in the brain increases SOCS3 expression and decreases the phosphorylation of STAT3, resulting in reducing IL-17A and IL-23, which suppress the differentiation and expansion of pathogenic Th17 cells, an important factor in MS development. These immune responses resulted in a reduction in the clinical scoring of EAE induced by myelin oligodendrocyte glycoprotein 35–55 immunization. In the EAE group with T. gondii infection (Tg + EAE group), Th17-related immune responses that exacerbate the onset of EAE were reduced compared to those in the EAE group. This study suggests that the alleviation of EAE after T. gondii infection is regulated in a SOCS3/STAT3/IL-17A/blood–brain barrier integrity-dependent manner. Although parasite infection would not be permitted for MS treatment, this study using T. gondii infection identified potential targets that contribute to disease attenuation.

scholarly journals Lack of NFATc1 SUMOylation prevents autoimmunity and alloreactivity

2020 ◽  
Vol 218 (1) ◽  
Author(s):  
Yin Xiao ◽  
Musga Qureischi ◽  
Lena Dietz ◽  
Martin Vaeth ◽  
Subrahmanya D. Vallabhapurapu ◽  
...  
Keyword(s):  
Transcription Factors ◽  
T Cell ◽  
Immune Responses ◽  
Inflammatory Diseases ◽  
Autoimmune Encephalomyelitis ◽  
Cell Responses ◽  
Ifn Γ ◽  
Experimental Autoimmune

Posttranslational modification with SUMO is known to regulate the activity of transcription factors, but how SUMOylation of individual proteins might influence immunity is largely unexplored. The NFAT transcription factors play an essential role in antigen receptor-mediated gene regulation. SUMOylation of NFATc1 represses IL-2 in vitro, but its role in T cell–mediated immune responses in vivo is unclear. To this end, we generated a novel transgenic mouse in which SUMO modification of NFATc1 is prevented. Avoidance of NFATc1 SUMOylation ameliorated experimental autoimmune encephalomyelitis as well as graft-versus-host disease. Elevated IL-2 production in T cells promoted T reg expansion and suppressed autoreactive or alloreactive immune responses. Mechanistically, increased IL-2 secretion counteracted IL-17 and IFN-γ expression through STAT5 and Blimp-1 induction. Then, Blimp-1 repressed IL-2 itself, as well as the induced, proliferation-associated survival factor Bcl2A1. Collectively, these data demonstrate that prevention of NFATc1 SUMOylation fine-tunes T cell responses toward lasting tolerance. Thus, targeting NFATc1 SUMOylation presents a novel and promising strategy to treat T cell–mediated inflammatory diseases.

scholarly journals CKD-506: A novel HDAC6-selective inhibitor that exerts therapeutic effects in a rodent model of multiple sclerosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Daekwon Bae ◽  
Ji-Young Lee ◽  
Nina Ha ◽  
Jinsol Park ◽  
Jiyeon Baek ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Immune Responses ◽  
Therapeutic Potential ◽  
Autoimmune Encephalitis ◽  
Selective Inhibitor ◽  
Therapeutic Effects ◽  
Treatment Regimens ◽  
Ifn Γ ◽  
Experimental Autoimmune

AbstractDespite advances in therapeutic strategies for multiple sclerosis (MS), the therapy options remain limited with various adverse effects. Here, the therapeutic potential of CKD-506, a novel HDAC6-selective inhibitor, against MS was evaluated in mice with myelin oligodendrocyte glycoprotein35–55 (MOG35–55)-induced experimental autoimmune encephalitis (EAE) under various treatment regimens. CKD-506 exerted prophylactic and therapeutic effects by regulating peripheral immune responses and maintaining blood–brain barrier (BBB) integrity. In MOG35–55-re-stimulated splenocytes, CKD-506 decreased proliferation and downregulated the expression of IFN-γ and IL-17A. CKD-506 downregulated the levels of pro-inflammatory cytokines in the blood of EAE mice. Additionally, CKD-506 decreased the leakage of intravenously administered Evans blue into the spinal cord; CD4+ T cells and CD4−CD11b+CD45+ macrophage/microglia in the spinal cord was also decreased. Moreover, CKD-506 exhibited therapeutic efficacy against MS, even when drug administration was discontinued from day 15 post-EAE induction. Disease exacerbation was not observed when fingolimod was changed to CKD-506 from day 15 post-EAE induction. CKD-506 alleviated depression-like behavior at the pre-symptomatic stage of EAE. In conclusion, CKD-506 exerts therapeutic effects by regulating T cell- and macrophage-mediated peripheral immune responses and strengthening BBB integrity. Our results suggest that CKD-506 is a potential therapeutic agent for MS.

scholarly journals 4-Ethylguaiacol modulates neuroinflammation and Th1/Th17 differentiation to ameliorate disease severity in experimental autoimmune encephalomyelitis

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Wen-Tsan Weng ◽  
Ping-Chang Kuo ◽  
Dennis A. Brown ◽  
Barbara A. Scofield ◽  
Destin Furnas ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Immune Responses ◽  
Disease Progression ◽  
Disease Severity ◽  
Autoimmune Encephalomyelitis ◽  
Relapsing Remitting ◽  
Th17 Differentiation ◽  
Experimental Autoimmune

Abstract Background Multiple sclerosis (MS) is a progressive autoimmune disease characterized by the accumulation of pathogenic inflammatory immune cells in the central nervous system (CNS) that subsequently causes focal inflammation, demyelination, axonal injury, and neuronal damage. Experimental autoimmune encephalomyelitis (EAE) is a well-established murine model that mimics the key features of MS. Presently, the dietary consumption of foods rich in phenols has been reported to offer numerous health benefits, including anti-inflammatory activity. One such compound, 4-ethylguaiacol (4-EG), found in various foods, is known to attenuate inflammatory immune responses. However, whether 4-EG exerts anti-inflammatory effects on modulating the CNS inflammatory immune responses remains unknown. Thus, in this study, we assessed the therapeutic effect of 4-EG in EAE using both chronic and relapsing-remitting animal models and investigated the immunomodulatory effects of 4-EG on neuroinflammation and Th1/Th17 differentiation in EAE. Methods Chronic C57BL/6 EAE and relapsing-remitting SJL/J EAE were induced followed by 4-EG treatment. The effects of 4-EG on disease progression, peripheral Th1/Th17 differentiation, CNS Th1/Th17 infiltration, microglia (MG) activation, and blood-brain barrier (BBB) disruption in EAE were evaluated. In addition, the expression of MMP9, MMP3, HO-1, and Nrf2 was assessed in the CNS of C57BL/6 EAE mice. Results Our results showed that 4-EG not only ameliorated disease severity in C57BL/6 chronic EAE but also mitigated disease progression in SJL/J relapsing-remitting EAE. Further investigations of the cellular and molecular mechanisms revealed that 4-EG suppressed MG activation, mitigated BBB disruption, repressed MMP3/MMP9 production, and inhibited Th1 and Th17 infiltration in the CNS of EAE. Furthermore, 4-EG suppressed Th1 and Th17 differentiation in the periphery of EAE and in vitro Th1 and Th17 cultures. Finally, we found 4-EG induced HO-1 expression in the CNS of EAE in vivo as well as in MG, BV2 cells, and macrophages in vitro. Conclusions Our work demonstrates that 4-EG confers protection against autoimmune disease EAE through modulating neuroinflammation and inhibiting Th1 and Th17 differentiation, suggesting 4-EG, a natural compound, could be potentially developed as a therapeutic agent for the treatment of MS/EAE.

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 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.

Propranolol Impairs Primary Immune Responses in Rat Experimental Autoimmune Encephalomyelitis

2019 ◽  
Vol 26 (3) ◽  
pp. 129-138 ◽  
Author(s):  
Ivan Pilipović ◽  
Ivana Vujnović ◽  
Raisa Petrović ◽  
Zorica Stojić-Vukanić ◽  
Gordana Leposavić
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Immune Responses ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune
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