Viral Infection of the Central Nervous System Exacerbates Interleukin-10 Receptor Deficiency-Mediated Colitis in SJL Mice.
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.
Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany.
Ann-Kathrin
AK
Uhde
Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany.|Center for Systems Neuroscience, Hannover, Germany.
Vanessa
V
Herder
Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany.|Center for Systems Neuroscience, Hannover, Germany.|Department of Pathobiology, Faculty of Veterinary & Animal Sciences, PMAS-Arid Agriculture University, Rawalpindi, Pakistan.
Muhammad
M
Akram Khan
Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany.|Center for Systems Neuroscience, Hannover, Germany.
Malgorzata
M
Ciurkiewicz
Fraunhofer-Institute for Toxicology and Experimental Medicine ITEM, Hannover, Germany.
Dirk
D
Schaudien
Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
René
R
Teich
Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
Stefan
S
Floess
Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany.|Center for Systems Neuroscience, Hannover, Germany.
Wolfgang
W
Baumgärtner
Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
Jochen
J
Huehn
Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany.|Center for Systems Neuroscience, Hannover, Germany.
Andreas
A
Beineke
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism* / Q000821:virology*; D003092:Colitis / Q000378:metabolism* / Q000473:pathology* / Q000821:virology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D018960:Hyaluronan Receptors / Q000378:metabolism; D037181:Lectins, C-Type; D051379:Mice; D053701:Receptors, Interleukin-10 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism; D017945:Theilovirus / Q000502:physiology; D000099192:CD69 Antigens
D000906:Antibodies; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D051858:Forkhead Transcription Factors; D018960:Hyaluronan Receptors; D037181:Lectins, C-Type; D053701:Receptors, Interleukin-10; D000099192:CD69 Antigens; C498833:Foxp3 protein, mouse