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Correction of all‐trans retinoic acid deficiency in alcoholic cirrhosis lessens the excessive inflammatory monocyte response: a translational study
Author(s) -
Ouziel Romy,
Trépo Eric,
Cremer Anneline,
Moreno Christophe,
Degré Delphine,
Chaouni Mustapha,
Vercruysse Vincent,
Quertinmont Eric,
Devière Jacques,
Lemmers Arnaud,
Gustot Thierry
Publication year - 2014
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.12249
Subject(s) - proinflammatory cytokine , medicine , alcoholic liver disease , peripheral blood mononuclear cell , immunology , immune system , tretinoin , monocyte , retinoic acid , vitamin , endocrinology , inflammation , cirrhosis , chemistry , in vitro , biochemistry , gene
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 NO 2 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.