Mice lacking Tbk1 activity exhibit immune cell infiltrates in multiple tissues and increased susceptibility to LPS-induced lethality
| Autor: | G. Roger Askew, Tianhui Zhou, Victoria Roberts, Katherine A. Fitzgerald, Lih-Ling Lin, Suzana Marusic, Vincent Ling, J. Perry Hall, Nancy L. Stedman, Zhaozhao Jiang, Paresh Thakker, Mark Ryan, Erica Marchlik, Wen Kuang, Richard Pfeifer, Stephen C. Benoit, Nadege Goutagny, Thaddeus Carlson |
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| Rok vydání: | 2010 |
| Předmět: |
Lipopolysaccharides
Male Necrosis Lipopolysaccharide Immunology Cell Inflammation Protein Serine-Threonine Kinases Biology Monocytes Proinflammatory cytokine Mice chemistry.chemical_compound Immune system medicine Animals Immunology and Allergy Chemokine CCL2 Monocyte Interferon-beta Cell Biology Molecular biology Mice Inbred C57BL medicine.anatomical_structure chemistry TLR4 Female Interferon Regulatory Factor-3 medicine.symptom |
| Zdroj: | Journal of Leukocyte Biology. 88:1171-1180 |
| ISSN: | 1938-3673 0741-5400 |
| DOI: | 10.1189/jlb.0210071 |
| Popis: | Mice lacking Tbk1 activity exhibit immune cell infiltrates in multiple tissues, altered circulating immune cell compartments, and increased susceptibility to LPS-induced lethality. 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 Tbk1Δ allele encodes a truncated Tbk1Δ protein that is catalytically inactive and expressed at very low levels. Upon LPS stimulation, macrophages from Tbk1Δ/Δ mice produce normal levels of proinflammatory cytokines (e.g., TNF-α), but IFN-β and RANTES expression and IRF3 DNA-binding activity are ablated. Three-month-old Tbk1Δ/Δ 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+/Δ littermates. Skin from 2-week-old Tbk1Δ/Δ mice is characterized by reactive changes, including hyperkeratosis, hyperplasia, necrosis, inflammatory cell infiltrates, and edema. In response to LPS challenge, 3-month-old Tbk1Δ/Δ mice die more quickly and in greater numbers than their Tbk1+/+ and Tbk1+/Δ counterparts. This lethality is accompanied by an overproduction of several proinflammatory cytokines in the serum of Tbk1Δ/Δ mice, including TNF-α, GM-CSF, IL-6, and KC. This overproduction of serum cytokines in Tbk1Δ/Δ 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. |
| Databáze: | OpenAIRE |
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