title: Paradoxical effects of all-trans-retinoic acid on lupus-like disease in the MRL/lpr mouse model.
abstract: Roles of all-trans-retinoic acid (tRA), a metabolite of vitamin A (VA), in both tolerogenic and immunogenic responses are documented. However, how tRA affects the development of systemic autoimmunity is poorly understood. Here we demonstrate that tRA have paradoxical effects on the development of autoimmune lupus in the MRL/lpr mouse model. We administered, orally, tRA or VA mixed with 10% of tRA (referred to as VARA) to female mice starting from 6 weeks of age. At this age, the mice do not exhibit overt clinical signs of lupus. However, the immunogenic environment preceding disease onset has been established as evidenced by an increase of total IgM/IgG in the plasma and expansion of lymphocytes and dendritic cells in secondary lymphoid organs. After 8 weeks of tRA, but not VARA treatment, significantly higher pathological scores in the skin, brain and lung were observed. These were accompanied by a marked increase in B-cell responses that included autoantibody production and enhanced expression of plasma cell-promoting cytokines. Paradoxically, the number of lymphocytes in the mesenteric lymph node decreased with tRA that led to significantly reduced lymphadenopathy. In addition, tRA differentially affected renal pathology, increasing leukocyte infiltration of renal tubulointerstitium while restoring the size of glomeruli in the kidney cortex. In contrast, minimal induction of inflammation with tRA in the absence of an immunogenic environment in the control mice was observed. Altogether, our results suggest that under a predisposed immunogenic environment in autoimmune lupus, tRA may decrease inflammation in some organs while generating more severe disease in others.
authors.affiliation: Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, 24061, United States of America.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Liao
authors.affiliation: Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, 24061, United States of America.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Ren
authors.affiliation: Department of Nutritional Sciences, Pennsylvania State University, University Park, PA, 16802, United States of America.
authors.forename: Cheng-Hsin
authors.initials: CH
authors.lastname: Wei
authors.affiliation: Department of Nutritional Sciences, Pennsylvania State University, University Park, PA, 16802, United States of America.
authors.forename: A Catharine
authors.initials: AC
authors.lastname: Ross
authors.affiliation: Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, 24061, United States of America.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Cecere
authors.affiliation: Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, 24061, United States of America.
authors.forename: Bernard S
authors.initials: BS
authors.lastname: Jortner
authors.affiliation: Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, 24061, United States of America.
authors.forename: S Ansar
authors.initials: SA
authors.lastname: Ahmed
authors.affiliation: Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, 24061, United States of America.
authors.forename: Xin M
authors.initials: XM
authors.lastname: Luo
mesh_terms: D000367:Age Factors; D000818:Animals; D015551:Autoimmunity / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D018836:Inflammation Mediators / Q000276:immunology; D007668:Kidney / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008206:Lymphatic Diseases / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D012867:Skin / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D018836:Inflammation Mediators; D014212:Tretinoin