Low dose zymosan ameliorates both chronic and relapsing experimental autoimmune encephalomyelitis

Li, Hongmei; Gonnella, Patricia; Safavi, Farinaz; Vessal, Ghazal; Nourbakhsh, Bardia; Zhou, Fang; Zhang, Guang Xian; Rostami, Abdolmohamad

doi:10.1016/j.jneuroim.2012.08.013

Cited by 24 publications

(24 citation statements)

References 51 publications

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“…In the present studies, we postulated that TLR tolerance could explain the TLR2 paradox in EAE as well as offer a potential mechanism for microbiome-mediated immune regulation. Our study differs from the polysaccharide A and zymosan studies (11)(12)(13)(14) in that we show TLR tolerance induction using a very low dose of a canonical TLR2 ligand and the microbiomederived TLR ligand known to access human serum, L654, attenuate EAE. Additionally, our study differs in our sole use of adoptive transfer EAE and in the effector and regulatory alterations we found associated with TLR tolerance-induced disease attenuation.…”

Section: Discussionmentioning

confidence: 58%

“…The TLR2 ligands, polysaccharide A and zymosan, when administered to mice during EAE (in the range of ∼100 mg per day), significantly reduced disease severity via induction of various subsets of Tregs (11)(12)(13)(14). In the present studies, we postulated that TLR tolerance could explain the TLR2 paradox in EAE as well as offer a potential mechanism for microbiome-mediated immune regulation.…”

Section: Discussionmentioning

confidence: 67%

“…In contrast to the potential requirement for TLR2 in the EAE disease process, other studies have reported that administering relatively large amounts of TLR2 ligands can attenuate EAE through induction of various Treg populations (11)(12)(13)(14). Thus, although the literature appears contradictory in suggesting both a requirement for and inhibitory capacity of TLR2 signaling in EAE, the concept of TLR tolerance can potentially resolve this paradox.…”

mentioning

confidence: 99%

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TLR Tolerance as a Treatment for Central Nervous System Autoimmunity

Anstadt

Fujiwara

Wasko

et al. 2016

The Journal of Immunology

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The role of TLR signaling in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) is unclear. This role is especially controversial in models of adoptive transfer EAE in which no adjuvant and no TLR ligands are administered. We recently reported that a microbiome-derived TLR2 ligand, Lipid 654 (L654), is present in healthy human serum but significantly decreased in the serum of MS patients. This suggested that microbiome products that gain access to the systemic circulation, rather than being proinflammatory, may normally play an immune-regulatory role by maintaining a state of relative TLR tolerance. Therefore, a loss of microbiome-mediated TLR tolerance, as suggested by lower serum levels of L654, may play a role in the pathogenesis of MS. As proof of concept we asked whether administering low-level TLR2 ligands in adoptive transfer EAE induces TLR2 tolerance and attenuates disease. We administered low-level Pam2CSK4 or L654 to mice receiving encephalitogenic cells and in doing so induced both TLR2 tolerance and attenuation of EAE. Disease attenuation was accompanied in the CNS by a decrease in macrophage activation, a decrease in a specific proinflammatory macrophage population, and a decrease in Th17 cells. In addition, disease attenuation was associated with an increase in splenic type 1 regulatory T cells. Kinetic tolerance induction studies revealed a critical period for TLR2 involvement in adoptive transfer EAE. Overall, these results suggest that inducing TLR tolerance may offer a new approach to treating CNS autoimmune diseases such as MS.

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 67%

mentioning

confidence: 99%

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TLR Tolerance as a Treatment for Central Nervous System Autoimmunity

Anstadt

Fujiwara

Wasko

et al. 2016

The Journal of Immunology

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“…Zymosan has been shown induce immune regulatory genes IL-10, vitamin A metabolizing enzyme (Aldh1a2) and TGF-β in DCs (18, 19, 21, 39) that enable them to induce Treg cells and suppress the differentiation of T H 1/T H 17 cells. Furthermore, our previous study has shown that β-catenin is critical for the induction of vitamin A metabolizing enzymes and IL-10 in mucosal DCs.…”

Section: Resultsmentioning

confidence: 99%

TLR2-Dependent Activation of β-Catenin Pathway in Dendritic Cells Induces Regulatory Responses and Attenuates Autoimmune Inflammation

Manoharan

Yuan

Suryawanshi

et al. 2014

The Journal of Immunology

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Dendritic cells (DCs) sense microbes via multiple innate receptors. Signals from different innate receptors are coordinated and integrated by DCs to generate specific innate and adaptive immune responses against pathogens. Previously, we have shown that two pathogen recognition receptors, TLR2 and dectin-1 that recognize the same microbial stimulus (zymosan) on DCs, induce mutually antagonistic regulatory or inflammatory responses, respectively. How diametric signals from these two receptors are coordinated in DCs to regulate or incite immunity is not known. Here we show that TLR2-signaling via AKT activates the β-catenin/TCF4 pathway in DCs and programs them to drive T regulatory cell differentiation. Activation of β-catenin/TCF4 was critical to induce regulatory molecules interleukin-10 (Il-10) and vitamin A metabolizing enzyme retinaldehyde dehydrogenase 2 (Aldh1a2) and to suppress pro-inflammatory cytokines. Deletion of β-catenin in DCs programmed them to drive TH17/TH1 cell differentiation in response to zymosan. Consistent with these findings, activation of the β-catenin pathway in DCs suppressed chronic inflammation and protected mice from TH17/TH1-mediated autoimmune neuroinflammation. Thus activation of β-catenin in DCs via the TLR2 receptor is a novel mechanism in DCs that regulates autoimmune inflammation.

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“…This gives α-lipoic acid an unusually broad spectrum of antioxidant action [22]. ALA has been termed the 'ideal' antioxidant, and it has been used in treating diseases in which oxidative stress plays a major role [27].…”

Section: Introductionmentioning

confidence: 99%

Antioxidative effects of α-lipoic acid in the brain, liver and kidneys in selected mouse organs exposed to zymosan

Goc¹,

Greń²,

Kapusta³

et al. 2015

Acta Biologica Hungarica

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This study investigated the role of exogenous α-lipoic acid (ALA) in the inflammation caused by zymosan application. Seventy-two adult male white mice were divided into twelve groups: three control groups, three Zymosan groups, three ALA groups and three groups being the combination of Zymosan and ALA. In the experimental groups, the animals were decapitated after 3, 6 and 24 hours after the injection. The activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were determined in the brain, liver and kidneys of the mice. After the injection of Zymosan, it was found that the activity of SOD, CAT and GSH-Px in the brain, liver and kidneys of mice was significantly lower in all time periods. The administration of ALA resulted in an opposite effect, namely, it increased the activity of the enzymes studied in the selected organs of mice. The Zymosan and ALA combination significantly inhibited the decrease in the activity of the enzymes compared with the values obtained in the groups of animals which received Zymosan only. The results of our study, using the Zymosan-induced inflammation, clearly indicate that ALA is an anti-inflammatory agent.

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Low dose zymosan ameliorates both chronic and relapsing experimental autoimmune encephalomyelitis

Cited by 24 publications

References 51 publications

TLR Tolerance as a Treatment for Central Nervous System Autoimmunity

TLR Tolerance as a Treatment for Central Nervous System Autoimmunity

TLR2-Dependent Activation of β-Catenin Pathway in Dendritic Cells Induces Regulatory Responses and Attenuates Autoimmune Inflammation

Antioxidative effects of α-lipoic acid in the brain, liver and kidneys in selected mouse organs exposed to zymosan

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