Suppression of experimental allergic encephalomyelitis by retinoic acid

Massacesi, Luca; Abbamondi, Anna Laura; Giorgi, Carla De; Sarlo, Francesco De; Lolli, Francesco; Amaducci, L.

doi:10.1016/0022-510x(87)90220-6

Cited by 46 publications

(22 citation statements)

References 19 publications

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“…These findings demonstrate that the induction of IL-4 production during EAE in WT mice did not substantially affect GM-CSF or IL-17 production, but instead caused increased RALDH activity in dendritic cells, thereby imprinting CD4 + T cells with gut-homing specificity. This treatment ultimately resulted in reduced EAE severity, thus providing a potentially new and simple therapeutic avenue for MS. was shown to be beneficial in EAE treatment (44), believed to be suppressive and able to shift the balance between Th17/iTreg cells (45), due in part to the high plasticity of these subsets (10). However, recent data suggest that iTreg cell generation and Th17 cell inhibition occur at high RA concentrations, while low physiological concentrations of RA support Th17 differentiation (46,47).…”

Section: Treatment Of Eae Wt Mice By Th2 Immunization or Il-4 Preventmentioning

confidence: 93%

Diverting T helper cell trafficking through increased plasticity attenuates autoimmune encephalomyelitis

Califano¹,

Sweeney²,

Lê³

et al. 2013

J. Clin. Invest.

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Naive T helper cells differentiate into functionally distinct effector subsets that drive specialized immune responses. Recent studies indicate that some of the effector subsets have plasticity. Here, we used an EAE model and found that Th17 cells deficient in the transcription factor BCL11B upregulated the Th2-associated proteins GATA3 and IL-4 without decreasing RAR-related orphan receptor γ (RORγt), IL-17, and GM-CSF levels. Surprisingly, abnormal IL-4 production affected Th17 cell trafficking, diverting migration from the draining lymph nodes/CNS route to the mesenteric lymph nodes/gut route, which ameliorated EAE without overt colitis. T helper cell rerouting in EAE was dependent on IL-4, which enhanced retinoic acid (RA) production by dendritic cells, which further induced expression of gut-homing receptors CCR9 and α 4 β 7 on Bcl11b-deficient CD4 + T cells. Furthermore, IL-4 treatment or Th2 immunization of wild-type mice with EAE caused no alteration in Th17 cytokines or RORγt, but diverted T helper cell trafficking to the gut, which improved EAE outcome without overt colitis. Our data demonstrate that Th17 cells are permissive to Th2 gene expression without affecting Th17 gene expression. This Th17 plasticity has an impact on trafficking, which is a critical component of the immune response and may represent a possible avenue for treating multiple sclerosis.

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Section: Treatment Of Eae Wt Mice By Th2 Immunization or Il-4 Preventmentioning

confidence: 93%

Diverting T helper cell trafficking through increased plasticity attenuates autoimmune encephalomyelitis

Califano¹,

Sweeney²,

Lê³

et al. 2013

J. Clin. Invest.

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“…In fact, ATRA analogs have shown efficacy in in vivo models of autoimmune disease. 23,25,26 This suggests that retinoid-based pharmaceutical strategies may offer a promising alternative to our current approach of managing immunologic diseases. It will be important to elucidate precisely how retinoids regulate IL-17 and FoxP3 to optimize therapeutic regimens and to generate agents with increased selectivity in these actions.…”

Section: Discussionmentioning

confidence: 99%

“…[23][24][25] For instance, ATRA has long been documented to inhibit EAE in animal models. 24,26 However, a mechanism underlying these findings has not been defined. In light of the recently recognized importance of Th17 and Treg cells in the pathophysiology of EAE, we explored a possible role for ATRA in Th17/Treg polarization.…”

Section: Introductionmentioning

confidence: 99%

Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway

Elias

Laurence

Davidson

et al. 2008

Blood

399

333

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IntroductionImmune responses are orchestrated by subsets of CD4 ϩ helper and effector T cells. Classically, differentiated T cells have been classified as belonging either to T-helper 1 (Th1) or Th2 lineages. 1 Th1 cells secrete interferon-gamma (IFN-␥) in response to interleukin-12 (IL-12) and require the transcription factors T-box21 (T-bet) and signal transducer and activator of transcription 4 (Stat4) 2 and Stat1, whereas Th2 cells secrete IL-4, IL-5, and IL-13 and require the transcription factors GATA-binding protein 3 (GATA-3) and Stat6. 3 While this simple paradigm was instrumental in understanding immune responses to model pathogens, it was less clear how such a model explained the pathogenesis of autoimmune disease.More recently, additional fates for CD4 ϩ T cells have emerged that provide more insights into the mechanisms of tolerance and immune-mediated disease. One of these new subsets of T cells, expressing the transcription factor FoxP3, is termed regulatory T cells (Tregs) and serves to inhibit immune responses. Deficiency of FoxP3 in mice and humans is associated with fatal autoimmune disease. 4,5 FoxP3 ϩ Tregs normally develop in the thymus, but FoxP3 expression and Treg function also develop when naive CD4 ϩ T cells are stimulated in vitro with transforming growth factor-␤1 (TGF-␤1) and IL-2. 6 Development and differentiation of Tregs and expression of FoxP3 are dependent upon another transcription factor, Stat5. 7,8 Another new subset of T cells that may be related to Tregs is a subset that produces the proinflammatory cytokine IL-17 (Th17 cells). Overproduction of IL-17 has been noted in a variety of models of autoimmune disease, including experimental autoimmune encephalomyelitis and collagen-induced arthritis. 9-13 Importantly, increased levels of IL-17 are also seen in human diseases, such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. 14-16 Th17 cells are generated by the cytokines TGF-␤1 and IL-6, the latter of which acts via Stat3 to induce the transcription factor retinoic acid orphan receptor gamma (ROR␥t). 17 Overexpression of ROR␥t induces IL-17 production, whereas deficiency of this transcription factor virtually abrogates Th17 differentiation.ROR␥t belongs to a superfamily of retinoid nuclear receptors that include the retinoic acid receptors (RARs), retinoid X receptors (RXRs), and other RORs. 18 A connection between retinoids and CD4 ϩ T-cell differentiation has long been recognized. Memory T cells from vitamin A-deficient mice have been found to overproduce . 19 In contrast, administration of the active metabolite of vitamin A, retinoic acid (RA), has been reported to suppress memory cell IFN-␥ production and increase IL-4 secretion. 20 Later, it emerged that vitamin A can be metabolized into retinoic acid isomers with different ligand-receptor affinities: 9-cis retinoic acid, with a higher affinity for the RXR family, and all-trans retinoic acid (ATRA), with a higher affinity for the RAR family. 21 Acting through RXR␣, 9-cis retinoic acid skews n...

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“…It was reported that AtRA or synthetic retinoids, including the RAR agonist Am80, improve the disease course of EAE (14,49,51,54,55). Agonists of PPARg and PPARd also ameliorate EAE through the inhibition of Th17 or Th1 differentiation (27)(28)(29).…”

Section: Discussionmentioning

confidence: 99%

Retinoid X Receptor Agonists Modulate Foxp3+ Regulatory T Cell and Th17 Cell Differentiation with Differential Dependence on Retinoic Acid Receptor Activation

Takeuchi

Yokota-Nakatsuma

Ohoka

et al. 2013

The Journal of Immunology

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Retinoic acid (RA) enhances TGF-β–dependent differentiation of Foxp3+ inducible regulatory T cells (iTregs) and inhibits Th17 differentiation by binding to the RA receptor (RAR)/retinoid X receptor (RXR) heterodimer. The major physiologic RA, all-trans-RA, binds to RAR but not to RXR at physiological concentrations. It remained unclear whether RXR-mediated stimulation affected the iTregs and Th17 differentiation. We found in this study that the RXR agonists, PA024 and tributyltin, augmented the ability of all-trans-RA or the RAR agonist Am80 to enhance CD4+CD25− T cells to acquire Foxp3 expression and suppressive function. However, they failed to enhance Foxp3 expression in the presence of the RAR antagonist LE540, suggesting that the effect depends on RAR-mediated signals. They exerted the effect largely by augmenting the ability of all-trans-RA to suppress the production of IL-4, IL-21, and IFN-γ that inhibited Foxp3 expression. Agonists of peroxisome proliferator-activated receptors and liver X receptors (LXRs), permissive partners of RXR, failed to enhance Foxp3 expression. In contrast, RXR agonists and LXR agonists suppressed IL-17 expression. The RXR-mediated suppression was not canceled by blocking RAR stimulation but was likely to involve permissive activation of LXRs. All-trans-RA and an agonist of RXR or LXR additively suppressed IL-17 expression when the all-trans-RA concentration was low. RXR agonists also suppressed Ccr6 expression that is essential for Th17 cells to enter the CNS. Accordingly, tributyltin treatment of mice ameliorated experimental autoimmune encephalomyelitis through regulating Th17 cell activities. These results suggest that RXR stimulation modulates Foxp3+ iTreg and Th17 differentiation with differential dependence on RAR-mediated stimulation.

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Suppression of experimental allergic encephalomyelitis by retinoic acid

Cited by 46 publications

References 19 publications

Diverting T helper cell trafficking through increased plasticity attenuates autoimmune encephalomyelitis

Diverting T helper cell trafficking through increased plasticity attenuates autoimmune encephalomyelitis

Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway

Retinoid X Receptor Agonists Modulate Foxp3+ Regulatory T Cell and Th17 Cell Differentiation with Differential Dependence on Retinoic Acid Receptor Activation

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