Paradoxical effects of all-trans-retinoic acid on lupus-like disease in the MRL/lpr mouse model

• Published in: PloS one Vol. 10; no. 3; p. e0118176
• Main Authors: Liao, Xiaofeng, Ren, Jingjing, Wei, Cheng-Hsin, Ross, A Catharine, Cecere, Thomas E, Jortner, Bernard S, Ahmed, S Ansar, Luo, Xin M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 16-03-2015; Public Library of Science (PLoS)
• Subjects: Acids; Age Factors; Analysis; Animals; Antigens; Autoantibodies; Autoimmune diseases; Autoimmunity; Autoimmunity - drug effects; B cells; Bone marrow; Brain; Brain - drug effects; Brain - immunology; Brain - pathology; Cytokines; Dendritic cells; Disease Models, Animal; Drug dosages; Female; Immune response; Immunogenicity; Immunoglobulin G; Immunoglobulin M; Immunology; Infiltration; Inflammation Mediators - immunology; Kidney - drug effects; Kidney - immunology; Kidney - pathology; Kidneys; Laboratory animals; Leukemia; Leukocytes; Leukocytes - drug effects; Leukocytes - immunology; Lung - drug effects; Lung - immunology; Lung - pathology; Lungs; Lupus; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - pathology; Lupus Erythematosus, Systemic - therapy; Lymph nodes; Lymphadenopathy; Lymphatic Diseases - drug therapy; Lymphatic Diseases - immunology; Lymphatic Diseases - pathology; Lymphocytes; Lymphocytes B; Metabolism; Metabolites; Mice; Mice, Inbred MRL lpr; Organs; Pathogenesis; Renal cortex; Retinoic acid; Rodents; Skin; Skin - drug effects; Skin - immunology; Skin - pathology; Systemic lupus erythematosus; Tretinoin; Tretinoin - pharmacology; Veterinary colleges; Veterinary medicine; Vitamin A; United States > US; Virginia; Pennsylvania
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0118176

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.