Correction of all-trans retinoic acid deficiency in alcoholic cirrhosis lessens the excessive inflammatory monocyte response: a translational study

Authors

  • Romy Ouziel,

    Corresponding author
    1. Laboratory of Experimental Gastroenterology, ULB, Brussels, Belgium
    2. Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, ULB, Brussels, Belgium
    • Correspondence

      Romy Ouziel, MD, Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles (ULB), Route de Lennik, 808 1070 Brussels, Belgium

      Tel: +32 2 555 61 96

      Fax: +32 2 555 61 97

      e-mail: romy.ouziel@erasme.ulb.ac.be

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  • Eric Trépo,

    1. Laboratory of Experimental Gastroenterology, ULB, Brussels, Belgium
    2. Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, ULB, Brussels, Belgium
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  • Anneline Cremer,

    1. Laboratory of Experimental Gastroenterology, ULB, Brussels, Belgium
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  • Christophe Moreno,

    1. Laboratory of Experimental Gastroenterology, ULB, Brussels, Belgium
    2. Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, ULB, Brussels, Belgium
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  • Delphine Degré,

    1. Laboratory of Experimental Gastroenterology, ULB, Brussels, Belgium
    2. Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, ULB, Brussels, Belgium
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  • Mustapha Chaouni,

    1. Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), ULB, Brussels, Belgium
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  • Vincent Vercruysse,

    1. Laboratory of Experimental Gastroenterology, ULB, Brussels, Belgium
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  • Eric Quertinmont,

    1. Laboratory of Experimental Gastroenterology, ULB, Brussels, Belgium
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  • Jacques Devière,

    1. Laboratory of Experimental Gastroenterology, ULB, Brussels, Belgium
    2. Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, ULB, Brussels, Belgium
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  • Arnaud Lemmers,

    1. Laboratory of Experimental Gastroenterology, ULB, Brussels, Belgium
    2. Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, ULB, Brussels, Belgium
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    • Both authors contributed equally to this work.
  • Thierry Gustot

    1. Laboratory of Experimental Gastroenterology, ULB, Brussels, Belgium
    2. Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, ULB, Brussels, Belgium
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    • Both authors contributed equally to this work.

Abstract

Background & Aims

Patients with alcoholic liver disease (ALD) have vitamin A (VA) deficiency and an enhanced immune response associated with disease severity. All-trans retinoic acid (ATRA), a VA-active metabolite, has anti-inflammatory effects and its deficiency could contribute to the exacerbated proinflammatory reaction. The aim of this study was to investigate the effects of ATRA/VA deficiency and supplementation on the monocyte response in ALD.

Methods

Vitamin A and ATRA plasma levels were quantified in ALD patients and healthy subjects (HS). The in vitro effect of ATRA on lipopolysaccharide (LPS)-induced TNF-α production by human peripheral blood mononuclear cells (PBMC) was assessed by ELISA and RT-PCR. The activation pattern of peritoneal macrophages (PerMΦ) and circulating monocytes isolated from VA-deficient mice and ALD patients, respectively, was evaluated by flow cytometry, quantification of TNF-α and NO2 production.

Results

Alcoholic liver disease patients (n = 85) showed plasmatic VA deficiency that was correlated with scores of severity and with the hepatic venous pressure gradient. ATRA levels correlated significantly with VA levels. In vitro, ATRA pretreatment decreased the overproduction of TNF-α by LPS-stimulated PBMC of ALD patients. In vivo, VA deficiency in mice was associated with increased activation of PerMΦ, while oral ATRA supplementation normalized it.

Conclusion

For the first time, we show that VA/ATRA deficiencies in ALD patients are associated with disease severity. Furthermore, our data strongly suggest that the VA deficiency observed in ALD patients might participate in the pathophysiology of the disease by priming immune cells, and that ATRA supplementation could downregulate the deleterious proinflammatory state in cirrhosis and might thus be of therapeutic use.

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