Abstract
Toll IL-1R 8/single Ig IL-1-related receptor (TIR8/SIGIRR) is a member of the IL-1R family, expressed by epithelial tissues and immature dendritic cells, and is regarded as a negative regulator of TLR/IL-1R signaling. Tir8-deficient mice were rapidly killed by intranasal administration of low doses of Mycobacterium tuberculosis, despite controlling efficiently the number of viable bacilli in different organs. Tir8(-/-)-infected mice showed an increased number of neutrophils and macrophages in the lungs; however, mycobacteria-specific CD4 and CD8 T cells were similar in Tir8(-/-) and Tir8(+/+) mice. Exaggerated mortality of Tir8(-/-) mice was due to massive liver necrosis and was accompanied by increased levels of IL-1beta and TNF-alpha in lung mononuclear cells and serum, as well as by increased production of IL-1beta and TNF-alpha by M. tuberculosis-infected dendritic cells in vitro. Accordingly, blocking IL-1beta and TNF-alpha with a mix of anti-cytokine Abs, significantly prolonged survival of Tir8(-/-) mice. Thus, TIR8/SIGIRR plays a key role in damping inflammation and tissue damage in M. tuberculosis infection.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies / pharmacology
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Cell Movement
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Cytokines / metabolism
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Dendritic Cells / immunology
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Dendritic Cells / microbiology
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Inflammation / genetics
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Inflammation / immunology
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Inflammation / microbiology
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Interleukin-1 / antagonists & inhibitors
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Interleukin-1 / blood
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Interleukin-1 / metabolism
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Interleukin-1beta / antagonists & inhibitors
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Interleukin-1beta / blood
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Interleukin-1beta / metabolism*
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Liver / immunology
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Liver / pathology
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Lung / immunology
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Macrophages, Alveolar / immunology
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Mice
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Mice, Mutant Strains
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Mycobacterium tuberculosis*
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Necrosis
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Neutrophils / immunology
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Receptors, Interleukin-1 / genetics
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Receptors, Interleukin-1 / physiology*
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Signal Transduction
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Toll-Like Receptors / metabolism
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Tuberculosis, Pulmonary / genetics*
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Tuberculosis, Pulmonary / immunology
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / blood
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Antibodies
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Cytokines
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Interleukin-1
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Interleukin-1beta
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Receptors, Interleukin-1
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Tir8 protein, mouse
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Toll-Like Receptors
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Tumor Necrosis Factor-alpha