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E3 ubiquitin ligase Cblb regulates the acute inflammatory response underlying lung injury

Nature Medicine volume 13, pages 920–926 (2007)Cite this article

Abstract

The E3 ubiquitin ligase Cblb has a crucial role in the prevention of chronic inflammation and autoimmunity. Here we show that Cblb also has an unexpected function in acute lung inflammation. Cblb attenuates the sequestration of inflammatory cells in the lungs after administration of lipopolysaccharide (LPS). In a model of polymicrobial sepsis in which acute lung inflammation depends on the LPS receptor (Toll-like receptor 4, TLR-4), the loss of Cblb expression accentuates acute lung inflammation and reduces survival. Loss of Cblb significantly increases sepsis-induced release of inflammatory cytokines and chemokines. Cblb controls the association between TLR4 and the intracellular adaptor MyD88. Expression of wild-type Cblb, but not expression of a Cblb mutant that lacks E3 ubiquitin ligase function, prevents the activity of a reporter gene for the transcription factor nuclear factor-κB (NF-κB) in monocytes that have been challenged with LPS. The downregulation of TLR4 expression on the cell surface of neutrophils is impaired in the absence of Cblb. Our data reveal that Cblb regulates the TLR4-mediated acute inflammatory response that is induced by sepsis.

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Figure 1: Genetic deletion of Cblb augments sepsis-induced acute lung inflammation and mortality.
Figure 2: Cblb regulates lung microvascular endothelial integrity and PMN activation in response to LPS challenge.
Figure 3: Cblb regulates NF-κB activation after LPS challenge.
Figure 4: Deletion of Cblb augments sepsis-induced cytokine and chemokine production.
Figure 5: Cblb regulates the association between TLR4 and MyD88 after LPS stimulation.

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Acknowledgements

We thank L.A. Benoit and K. Wary for discussions, K. Price for critical reading of the manuscript, Y. Wu for technical assistance, and S. Lipkowitz of the US National Cancer Institute for Cblb expression vector constructs. This work was supported by US National Institutes of Health grants P01 HL77806, PO1 HL60678 and T32 HL 07829.

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  1. Kurt Bachmaier and Sophie Toya: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, College of Medicine, University of Illinois, E403, Medical Science Building, M/C 868, 835 S. Wolcott Avenue, Chicago, 60612, Illinois, USA

    Kurt Bachmaier, Sophie Toya, Xiaopei Gao, Thomas Triantafillou, Sean Garrean, Randall S Frey, Stephen Vogel, Richard Minshall, John W Christman, Chinnaswamy Tiruppathi & Asrar B Malik

  2. Department of Medicine and Center of Lung and Vascular Biology, College of Medicine, University of Illinois, E403, Medical Science Building, M/C 868, 835 S. Wolcott Avenue, Chicago, 60612, Illinois, USA

    Sophie Toya, Gye Young Park, John W Christman & Asrar B Malik

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Bachmaier, K., Toya, S., Gao, X. et al. E3 ubiquitin ligase Cblb regulates the acute inflammatory response underlying lung injury. Nat Med 13, 920–926 (2007). https://doi.org/10.1038/nm1607

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