Mice lacking Tbk1 activity exhibit immune cell infiltrates in multiple tissues and increased susceptibility to LPS-induced lethality
Department of Medicine, Division of Infectious Diseases and Immunology
Animals; Chemokine CCL2; Female; Interferon Regulatory Factor-3; Interferon-beta; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Monocytes; Protein-Serine-Threonine Kinases
TBK1 is critical for immunity against microbial pathogens that activate TLR4- and TLR3-dependent signaling pathways. To address the role of TBK1 in inflammation, mice were generated that harbor two copies of a mutant Tbk1 allele. This Tbk1(Delta) allele encodes a truncated Tbk1(Delta) protein that is catalytically inactive and expressed at very low levels. Upon LPS stimulation, macrophages from Tbk1(Delta/Delta) mice produce normal levels of proinflammatory cytokines (e.g., TNF-alpha), but IFN-beta and RANTES expression and IRF3 DNA-binding activity are ablated. Three-month-old Tbk1(Delta/Delta) mice exhibit mononuclear and granulomatous cell infiltrates in multiple organs and inflammatory cell infiltrates in their skin, and they harbor a 2-fold greater amount of circulating monocytes than their Tbk1(+/+) and Tbk1(+/Delta) littermates. Skin from 2-week-old Tbk1(Delta/Delta) mice is characterized by reactive changes, including hyperkeratosis, hyperplasia, necrosis, inflammatory cell infiltrates, and edema. In response to LPS challenge, 3-month-old Tbk1(Delta/Delta) mice die more quickly and in greater numbers than their Tbk1(+/+) and Tbk1(+/Delta) counterparts. This lethality is accompanied by an overproduction of several proinflammatory cytokines in the serum of Tbk1(Delta/Delta) mice, including TNF-alpha, GM-CSF, IL-6, and KC. This overproduction of serum cytokines in Tbk1(Delta/Delta) mice following LPS challenge and their increased susceptibility to LPS-induced lethality may result from the reactions of their larger circulating monocyte compartment and their greater numbers of extravasated immune cells.
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Citation: J Leukoc Biol. 2010 Dec;88(6):1171-80. Epub 2010 Jul 22. Link to article on publisher's site
Marchlik, Erica; Thakker, Paresh; Carlson, Thaddeus; Jiang, Zhaozhao; Ryan, Mark; Marusic, Suzana; Goutagny, Nadege; Kuang, Wen; Askew, G. Roger; Roberts, Victoria; Benoit, Stephen; Zhou, Tianhui; Ling, Vincent; Pfeifer, Richard; Stedman, Nancy; Fitzgerald, Katherine A.; Lin, Lih-Ling; and Hall, J. Perry, "Mice lacking Tbk1 activity exhibit immune cell infiltrates in multiple tissues and increased susceptibility to LPS-induced lethality" (2010). Infectious Diseases and Immunology Publications and Presentations. 112.