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Mice lacking Tbk1 activity exhibit immune cell infiltrates in multiple tissues 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 Tbk1(Δ) allele encodes a truncated Tbk1(Δ) protein that is catalytically inactive and expressed at very low levels. Upon LPS stimulation, macrophages from Tbk1(Δ/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 Tbk1(Δ/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 Tbk1(Δ/Δ) mice is characterized by reactive changes, including hyperkeratosis, hyperplasia, necrosis, inflammatory cell infiltrates, and edema. In response to LPS challenge, 3-month-old Tbk1(Δ/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 Tbk1(Δ/Δ) mice, including TNF-α, GM-CSF, IL-6, and KC. This overproduction of serum cytokines in Tbk1(Δ/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.

Pubmed ID: 20651301


  • Marchlik E
  • Thakker P
  • Carlson T
  • Jiang Z
  • Ryan M
  • Marusic S
  • Goutagny N
  • Kuang W
  • Askew GR
  • Roberts V
  • Benoit S
  • Zhou T
  • Ling V
  • Pfeifer R
  • Stedman N
  • Fitzgerald KA
  • Lin LL
  • Hall JP


Journal of leukocyte biology

Publication Data

December 2, 2010

Associated Grants


Mesh Terms

  • Animals
  • Chemokine CCL2
  • Female
  • Interferon Regulatory Factor-3
  • Interferon-beta
  • Lipopolysaccharides
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Monocytes
  • Protein-Serine-Threonine Kinases