Viral Infection of the Central Nervous System Exacerbates Interleukin-10 Receptor Deficiency-Mediated Colitis in SJL Mice

• Published in: PloS one 2016-09, Vol.11 (9), p.e0161883
• Main Authors: Uhde, Ann-Kathrin, Herder, Vanessa, Akram Khan, Muhammad, Ciurkiewicz, Malgorzata, Schaudien, Dirk, Teich, René, Floess, Stefan, Baumgärtner, Wolfgang, Huehn, Jochen, Beineke, Andreas
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antibodies - pharmacology; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Autoimmune diseases; B cells; Biology and Life Sciences; Blocking antibodies; CD3 antigen; CD3 Complex - metabolism; CD4 antigen; CD4-Positive T-Lymphocytes - metabolism; CD44 antigen; CD69 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - metabolism; Cell activation; Central nervous system; Central Nervous System - metabolism; Central Nervous System - virology; Chronic infection; Colitis; Colitis - metabolism; Colitis - pathology; Colitis - virology; Cytotoxicity; Demyelination; Disorders; Female; Forkhead Transcription Factors - metabolism; Foxp3 protein; Gastrointestinal diseases; Helper cells; Homeostasis; Hyaluronan Receptors - metabolism; Immune response; Immunological memory; Immunological tolerance; Immunosuppression; Infection; Infectious diseases; Inflammatory bowel disease; Inflammatory bowel diseases; Interleukin; Interleukin 10; Interleukins; Intestine; Lectins, C-Type; Lymphocytes; Lymphocytes T; Medical research; Medicine and Health Sciences; Mice; Mortality; Multiple sclerosis; Nervous system diseases; Neurological diseases; Neutralization; Pathology; Receptors, Interleukin-10 - antagonists & inhibitors; Receptors, Interleukin-10 - deficiency; Receptors, Interleukin-10 - metabolism; Research and Analysis Methods; Rodents; Signaling; Spinal cord; T cells; T-Lymphocytes - metabolism; Theilovirus - physiology; Viruses
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0161883

Theiler´s murine encephalomyelitis virus (TMEV)-infection is a widely used animal model for studying demyelinating disorders, including multiple sclerosis (MS). The immunosuppressive cytokine Interleukin (IL)-10 counteracts hyperactive immune responses and critically controls immune homeostasis in infectious and autoimmune disorders. In order to investigate the effect of signaling via Interleukin-10 receptor (IL-10R) in infectious neurological diseases, TMEV-infected SJL mice were treated with IL-10R blocking antibody (Ab) in the acute and chronic phase of the disease. The findings demonstrate that (i) Ab-mediated IL-10 neutralization leads to progressive colitis with a reduction in Foxp3+ regulatory T cells and increased numbers of CD8+CD44+ memory T cells as well as activated CD4+CD69+ and CD8+CD69+ T cells in uninfected mice. (ii) Concurrent acute TMEV-infection worsened enteric disease-mediated by IL-10R neutralization. Virus-triggered effects were associated with an enhanced activation of CD4+ T helper cells and CD8+ cytotoxic T lymphocytes and augmented cytokine expression. By contrast, (iii) IL-10R neutralization during chronic TMEV-infection was not associated with enhanced peripheral immunopathology but an increased CD3+ T cell influx in the spinal cord. IL-10R neutralization causes a breakdown in peripheral immune tolerance in genetically predisposed mice, which leads to immune-mediated colitis, resembling inflammatory bowel disease. Hyperactive immune state following IL-10R blockade is enhanced by central nervous system-restricted viral infection in a disease phase-dependent manner.