scholarly journals Tryptophan hydroxylase-1 regulates immune tolerance and inflammation

2012 ◽  
Vol 209 (11) ◽  
pp. 2127-2135 ◽  
Author(s):  
Elizabeth C. Nowak ◽  
Victor C. de Vries ◽  
Anna Wasiuk ◽  
Cory Ahonen ◽  
Kathryn A. Bennett ◽  
...  
Keyword(s):  
Immune Tolerance ◽  
Tryptophan Hydroxylase ◽  
Inflammatory Responses ◽  
Essential Amino Acids ◽  
The Novel ◽  
Skin Allograft ◽  
Autoimmune Encephalomyelitis ◽  
Tumor Remission ◽  
Experimental Autoimmune

Nutrient deprivation based on the loss of essential amino acids by catabolic enzymes in the microenvironment is a critical means to control inflammatory responses and immune tolerance. Here we report the novel finding that Tph-1 (tryptophan hydroxylase-1), a synthase which catalyses the conversion of tryptophan to serotonin and exhausts tryptophan, is a potent regulator of immunity. In models of skin allograft tolerance, tumor growth, and experimental autoimmune encephalomyelitis, Tph-1 deficiency breaks allograft tolerance, induces tumor remission, and intensifies neuroinflammation, respectively. All of these effects of Tph-1 deficiency are independent of its downstream product serotonin. Because mast cells (MCs) appear to be the major source of Tph-1 and restoration of Tph-1 in the MC compartment in vivo compensates for the defect, these experiments introduce a fundamentally new mechanism of MC-mediated immune suppression that broadly impacts multiple arms of immunity.

scholarly journals Tim-3 Relieves Experimental Autoimmune Encephalomyelitis by Suppressing MHC-II

2022 ◽  
Vol 12 ◽  
Author(s):  
Lili Tang ◽  
Ge Li ◽  
Yang Zheng ◽  
Chunmei Hou ◽  
Yang Gao ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cell ◽  
Experimental Autoimmune Encephalomyelitis ◽  
T Cell Activation ◽  
Immune Tolerance ◽  
Cell Activation ◽  
Autoimmune Encephalomyelitis ◽  
Mhc Ii ◽  
Experimental Autoimmune

Tim-3, an immune checkpoint inhibitor, is widely expressed on the immune cells and contributes to immune tolerance. However, the mechanisms by which Tim-3 induces immune tolerance remain to be determined. Major histocompatibility complex II (MHC-II) plays a key role in antigen presentation and CD4+T cell activation. Dysregulated expressions of Tim-3 and MHC-II are associated with the pathogenesis of many autoimmune diseases including multiple sclerosis. Here we demonstrated that, by suppressing MHC-II expression in macrophages via the STAT1/CIITA pathway, Tim-3 inhibits MHC-II-mediated autoantigen presentation and CD4+T cell activation. As a result, overexpression or blockade of Tim-3 signaling in mice with experimental autoimmune encephalomyelitis (EAE) inhibited or increased MHC-II expression respectively and finally altered clinical outcomes. We thus identified a new mechanism by which Tim-3 induces immune tolerance in vivo and regulating the Tim-3-MHC-II signaling pathway is expected to provide a new solution for multiple sclerosis treatment.

scholarly journals Modulation of experimental autoimmune encephalomyelitis through TRAF3-mediated suppression of interleukin 17 receptor signaling

2010 ◽  
Vol 207 (12) ◽  
pp. 2647-2662 ◽  
Author(s):  
Shu Zhu ◽  
Wen Pan ◽  
Peiqing Shi ◽  
Hanchao Gao ◽  
Fang Zhao ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Inflammatory Cytokine ◽  
Inflammatory Responses ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Interleukin 17 ◽  
Receptor Signaling ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

Interleukin 17 (IL-17) plays critical roles in the pathogenesis of various autoimmune diseases, including experimental autoimmune encephalomyelitis (EAE). How the signals triggered by this powerful inflammatory cytokine are controlled to avoid abnormal inflammatory responses is not well understood. In this study, we report that TRAF3 is a receptor proximal negative regulator of IL-17 receptor (IL-17R) signaling. TRAF3 greatly suppressed IL-17–induced NF-κB and mitogen-activated protein kinase activation and subsequent production of inflammatory cytokines and chemokines. Mechanistically, the binding of TRAF3 to IL-17R interfered with the formation of the receptor signaling activation complex IL-17R–Act1–TRAF6, resulting in suppression of downstream signaling. TRAF3 markedly inhibited IL-17–induced expression of inflammatory cytokine and chemokine genes in vivo and consequently delayed the onset and greatly reduced the incidence and severity of EAE. Thus, TRAF3 is a negative regulator of IL-17R proximal signaling.

scholarly journals MeCP2 deficiency exacerbates the neuroinflammatory setting and autoreactive response during an autoimmune challenge

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
M. I. Zalosnik ◽  
M. C. Fabio ◽  
M. L. Bertoldi ◽  
C. N. Castañares ◽  
A. L. Degano
Keyword(s):  
Immune Activation ◽  
Inflammatory Responses ◽  
Active Role ◽  
Autoimmune Encephalomyelitis ◽  
Immune Alterations ◽  
Anti Inflammatory ◽  
Novel Therapeutic Strategies ◽  
Experimental Autoimmune

AbstractRett syndrome is a severe and progressive neurological disorder linked to mutations in the MeCP2 gene. It has been suggested that immune alterations may play an active role in the generation and/or maintenance of RTT phenotypes. However, there is no clear consensus about which pathways are regulated in vivo by MeCP2 in the context of immune activation. In the present work we set to characterize the role of MeCP2 during the progression of Experimental Autoimmune Encephalomyelitis (EAE) using the MeCP2308/y mouse model (MUT), which represents a condition of “MeCP2 function deficiency”. Our results showed that MeCP2 deficiency increased the susceptibility to develop EAE, along with a defective induction of anti-inflammatory responses and an exacerbated MOG-specific IFNγ expression in immune sites. In MUT-EAE spinal cord, we found a chronic increase in pro-inflammatory cytokines gene expression (IFNγ, TNFα and IL-1β) and downregulation of genes involved in immune regulation (IL-10, FoxP3 and CX3CR1). Moreover, our results indicate that MeCP2 acts intrinsically upon immune activation, affecting neuroimmune homeostasis by regulating the pro-inflammatory/anti-inflammatory balance in vivo. These results are relevant to identify the potential consequences of MeCP2 mutations on immune homeostasis and to explore novel therapeutic strategies for MeCP2-related disorders.

scholarly journals Toll-like receptor-9 stimulated plasmacytoid dendritic cell precursors suppress autoimmune neuroinflammation in a murine model of multiple sclerosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hélène Letscher ◽  
Viviane A. Agbogan ◽  
Sarantis Korniotis ◽  
Pauline Gastineau ◽  
Emmanuel Tejerina ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Plasmacytoid Dendritic Cell ◽  
Toll Like Receptor ◽  
Hematopoietic Progenitors ◽  
Autoimmune Encephalomyelitis ◽  
Hematopoietic Precursor ◽  
Therapeutic Properties ◽  
Experimental Autoimmune

AbstractEarly innate education of hematopoietic progenitors within the bone marrow (BM) stably primes them for either trained immunity or instead immunoregulatory functions. We herein demonstrate that in vivo or in vitro activation within the BM via Toll-like receptor-9 generates a population of plasmacytoid dendritic cell (pDC) precursors (CpG-pre-pDCs) that, unlike pDC precursors isolated from PBS-incubated BM (PBS-pre-pDCs), are endowed with the capacity to halt progression of ongoing experimental autoimmune encephalomyelitis. CpG activation enhances the selective migration of pDC precursors to the inflamed spinal cord, induces their immediate production of TGF-β, and after migration, of enhanced levels of IL-27. CpG-pre-pDC derived TGF-β and IL-27 ensure protection at early and late phases of the disease, respectively. Spinal cords of CpG-pre-pDC-protected recipient mice display enhanced percentages of host-derived pDCs expressing TGF-β as well as an accumulation of IL-10 producing B cells and of CD11c+ CD11b+ dendritic cells. These results reveal that pDC precursors are conferred stable therapeutic properties by early innate activation within the BM. They further extend to the pDC lineage promising perspectives for cell therapy of autoimmune diseases with innate activated hematopoietic precursor cells.

scholarly journals Interleukin-19 Abrogates Experimental Autoimmune Encephalomyelitis by Attenuating Antigen-Presenting Cell Activation

2021 ◽  
Vol 12 ◽  
Author(s):  
Hiroshi Horiuchi ◽  
Bijay Parajuli ◽  
Hiroyasu Komiya ◽  
Yuki Ogawa ◽  
Shijie Jin ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Mhc Class Ii ◽  
Th17 Cell ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Autoimmune Encephalomyelitis ◽  
Therapeutic Benefits ◽  
Ms Pathogenesis ◽  
Experimental Autoimmune

Interleukin-19 (IL-19) acts as a negative-feedback regulator to limit proinflammatory response of macrophages and microglia in autocrine/paracrine manners in various inflammatory diseases. Multiple sclerosis (MS) is a major neuroinflammatory disease in the central nervous system (CNS), but it remains uncertain how IL-19 contributes to MS pathogenesis. Here, we demonstrate that IL-19 deficiency aggravates experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, by promoting IL-17-producing helper T cell (Th17 cell) infiltration into the CNS. In addition, IL-19-deficient splenic macrophages expressed elevated levels of major histocompatibility complex (MHC) class II, co-stimulatory molecules, and Th17 cell differentiation-associated cytokines such as IL-1β, IL-6, IL-23, TGF-β1, and TNF-α. These observations indicated that IL-19 plays a critical role in suppression of MS pathogenesis by inhibiting macrophage antigen presentation, Th17 cell expansion, and subsequent inflammatory responses. Furthermore, treatment with IL-19 significantly abrogated EAE. Our data suggest that IL-19 could provide significant therapeutic benefits in patients with MS.

In vivo molecular imaging of adhesion molecules in experimental autoimmune encephalomyelitis (EAE)

2005 ◽  
Vol 25 (3) ◽  
pp. 199-205 ◽  
Author(s):  
Ralf A. Linker ◽  
Michael Reinhardt ◽  
Martin Bendszus ◽  
Gesa Ladewig ◽  
Andreas Briel ◽  
...  
Keyword(s):  
Molecular Imaging ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Adhesion Molecules ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune
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