Retinoic Acid Reduces Autoimmune Renal Injury and Increases Survival in NZB/W F1 Mice

Kinoshita, Koji; Yoo, B.-S.; Nozaki, Yuji; Sugiyama, Masafumi; Ikoma, Shinya; Ohno, Motoki; Funauchi, Masanori; Kanamaru, Akihisa

doi:10.4049/jimmunol.170.11.5793

Cited by 78 publications

(76 citation statements)

References 42 publications

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“…Disease-, sex-, and time-dependent differences were identified. Using vitamin A as a potential intervention to reduce lupus nephritis (29)(30)(31)(32), we also showed that specific changes of the gut microbiota strongly correlated with disease attenuation. Predicted metagenomes associated with murine lupus and vitamin A treatments were also described.…”

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confidence: 91%

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Dynamics of Gut Microbiota in Autoimmune Lupus

Zhang

Liao

Sparks

et al. 2014

Appl Environ Microbiol

265

276

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Gut microbiota has been recognized as an important environmental factor in health, as well as in metabolic and immunological diseases, in which perturbation of the host gut microbiota is often observed in the diseased state. However, little is known on the role of gut microbiota in systemic lupus erythematosus. We investigated the effects of host genetics, sex, age, and dietary intervention on the gut microbiome in a murine lupus model. In young, female lupus-prone mice resembling women at childbearing age, a population with the highest risk for lupus, we found marked depletion of lactobacilli, and increases in Lachnospiraceae and overall diversity compared to age-matched healthy controls. The predicted metagenomic profile in lupus-prone mice showed a significant enrichment of bacterial motility-and sporulation-related pathways. Retinoic acid as a dietary intervention restored lactobacilli that were downregulated in lupus-prone mice, and this correlated with improved symptoms. The predicted metagenomes also showed that retinoic acid reversed many lupus-associated changes in microbial functions that deviated from the control. In addition, gut microbiota of lupus-prone mice were different between sexes, and an overrepresentation of Lachnospiraceae in females was associated with an earlier onset of and/or more severe lupus symptoms. Clostridiaceae and Lachnospiraceae, both harboring butyrate-producing genera, were more abundant in the gut of lupus-prone mice at specific time points during lupus progression. Together, our results demonstrate the dynamics of gut microbiota in murine lupus and provide evidence to suggest the use of probiotic lactobacilli and retinoic acid as dietary supplements to relieve inflammatory flares in lupus patients.

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confidence: 91%

“…Vitamin A has been shown to reduce lupus nephritis (29)(30)(31)(32). However, while orally administered vitamin A may come directly in contact with commensal bacteria in the intestinal tract during absorption, little is known about whether and how this nutrient affects gut microbiota.…”

Section: Lupus-associated Gut Microbial Composition and Diversitymentioning

confidence: 99%

Dynamics of Gut Microbiota in Autoimmune Lupus

Zhang

Liao

Sparks

et al. 2014

Appl Environ Microbiol

265

276

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“…Ig class-specific anti-DNA Abs were measured by ELISA as described previously (24). Each well of flat-bottom 96-well plates (Costar, Cambridge, MA) was coated with calf thymus DNA (Sigma-Aldrich, St. Louis, MO), dried at 37°C, and washed in isotonic PBS (pH 7.4).…”

Section: Anti-dna Absmentioning

confidence: 99%

Blockade of IL-18 Receptor Signaling Delays the Onset of Autoimmune Disease in MRL-Fas lpr Mice

Kinoshita

Yamagata

Nozaki

et al. 2004

The Journal of Immunology

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Autoimmune disease in Fas-deficient MRL-Faslpr mice is dependent on infiltrating autoreactive leukocytes and autoantibodies, and IFN-γ plays an important role in the pathogenesis. As IL-18 is capable of inducing IFN-γ production in T cells, we hypothesized that signaling through IL-18R is involved in the pathogenesis. To investigate the impact of IL-18 in this autoimmune disease, we generated an MRL-Faslpr strain deficient in IL-18Rα. Compared with the wild-type strain, IL-18Rα-deficient MRL-Faslpr mice survived longer and showed a significant reduction in renal pathology, including glomerular IgG deposits, proteinuria, and serum anti-DNA Abs. Intrarenal transcripts encoding IFN-γ, TNF-α, IL-12, and IL-10, which have been linked to nephritis, were all markedly reduced. Skin lesions, lymphadenopathy, and lung pathology characteristic of the MRL-Faslpr mouse disease were diminished in IL-18Rα-deficient MRL-Faslpr mice. Thus, we conclude that IL-18Rα signaling is critical to the pathogenesis of autoimmune disease in MRL-Faslpr mice.

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“…It can promote anti-inflammatory Foxp3-expressing regulatory T cells and suppress proinflammatory Th17 cells (12,13). Regarding the effect of retinoic acid on autoimmune diseases, a few reports have shown the therapeutic efficacy of retinoic acid in animal models of multiple sclerosis (14) and systemic lupus erythematosus (15,16). As for the role of retinoic acid in RA, which is the prototype of autoimmune diseases, a few investigations have shown that retinoic acid had a therapeutic impact on animal models of RA (17)(18)(19)(20).…”

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confidence: 99%

Retinoic Acid Attenuates Rheumatoid Inflammation in Mice

Kwok

Park

Cho

et al. 2012

The Journal of Immunology

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Retinoic acid is the active vitamin A derivative and is well-known to have diverse immunomodulatory actions. In this study, we investigated the impact of all-trans retinoic acid (ATRA), a biologic key metabolite of vitamin A, on the development of arthritis and the pathophysiologic mechanisms by which ATRA might have antiarthritic effects in animal model of rheumatoid arthritis (RA; collagen-induced arthritis [CIA] in DBA/1J mice). We showed that treatment with ATRA markedly suppressed the clinical and histologic signs of arthritis in the CIA mice. It reduced the expression of IL-17 in the arthritic joints. Interestingly, Foxp3+ regulatory T cells were markedly increased and IL-17–producing CD4+ T cells (Th17 cells) were decreased in the spleens of ATRA-treated mice. In vitro treatment with ATRA induced the expression of Foxp3 and repressed the IL-17 expression in the CD4+ T cells in mice. ATRA suppressed the production of total IgG and IgG2a in splenocytes that were stimulated by LPS. It also reduced serum levels of total IgG and IgG2 anti-collagen Abs and germinal center formation in CIA mice. In addition, the ATRA-treated mice showed decreased osteoclast formation in arthritic joints. Moreover, ATRA downregulated the expression of receptor activator of NF-κB ligand, the leading player of osteoclastogenesis, in the CD4+ T cells and fibroblast-like synoviocytes from patients with RA. Furthermore, ATRA prevented both human monocytes and mice bone marrow-derived monocytes/macrophage cells from differentiating into osteoclasts. These data suggest ATRA might be an effective treatment modality for RA patients.

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Retinoic Acid Reduces Autoimmune Renal Injury and Increases Survival in NZB/W F1 Mice

Cited by 78 publications

References 42 publications

Dynamics of Gut Microbiota in Autoimmune Lupus

Dynamics of Gut Microbiota in Autoimmune Lupus

Blockade of IL-18 Receptor Signaling Delays the Onset of Autoimmune Disease in MRL-Fas lpr Mice

Retinoic Acid Attenuates Rheumatoid Inflammation in Mice

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