Th17 development and autoimmune arthritis in the absence of reactive oxygen species.
Dendritic cells (DC) express a functional NADPH oxidase and produce reactive oxygen species (ROS) upon interaction with microbes and T cells. Exposure to ROS leads to DC activation and maturation, as evidenced by phenotypic and functional changes. We have evaluated how endogenous ROS production affects the cytokine secretion pattern and T cell-activating capacity of bone marrow-derived murine DC. DC treated with ROS scavengers, as well as DC from mice that lack a functional NADPH oxidase (and thereby inherently deficient in ROS production) produced significantly increased levels of IL-1beta, IL-6, TNF-alpha and TGF-beta in response to microbial activation. DC deficient in ROS production induced high levels of IFN-gamma and IL-17 in responding T cells after Ag-specific or superantigen-induced activation. Finally, we show that ROS deficiency affected the induction of a T cell-dependent inflammatory condition, collagen-induced arthritis (CIA). C57BL/6 mice that lack a functional NADPH oxidase developed a severe and erosive CD4-dependent CIA, whereas the majority of the congenic wild-type animals remained healthy. These data suggest that ROS act as immunomodulators in DC-driven T cell activation and perhaps also in T cell-dependent immunopathology.
George-Chandy
Annie
A
Department of Rheumatology and Inflammation Research, Division of Medicine, Göteborg University, Göteborg, Sweden.
Nordström
Inger
I
Nygren
Erik
E
Jonsson
Ing-Marie
IM
Postigo
Jorge
J
Collins
Laurence Vincent
LV
Eriksson
Kristina
K
D000818:Animals; D001168:Arthritis / Q000378:metabolism*; D001327:Autoimmune Diseases / Q000276:immunology* / Q000378:metabolism*; D024043:Collagen Type II / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D006105:Granulomatous Disease, Chronic / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism*
D024043:Collagen Type II; D020381:Interleukin-17; D017382:Reactive Oxygen Species; D007371:Interferon-gamma; D019255:NADPH Oxidases