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Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b

Nature Immunology volume 11, pages 734–742 (2010)Cite this article

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Abstract

Integrins are critical for the migration and function of leukocytes in inflammation. However, the interaction between integrin αM (CD11b), which has high expression in monocytes and macrophages, and Toll-like receptor (TLR)-triggered innate immunity remains unclear. Here we report that CD11b deficiency enhanced TLR-mediated responses in macrophages, rendering mice more susceptible to endotoxin shock and Escherichia coli–caused sepsis. CD11b was activated by TLR-triggered phosphatidylinositol 3-OH kinase (PI(3)K) and the effector RapL and fed back to inhibit TLR signaling by activating the tyrosine kinases Src and Syk. Syk interacted with and induced tyrosine phosphorylation of MyD88 and TRIF, which led to degradation of these adaptor molecules by the E3 ubiquitin ligase Cbl-b. Thus, TLR-triggered, active CD11b integrin engages in crosstalk with the MyD88 and TRIF pathways and subsequently inhibits TLR signaling in innate immune responses.

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Figure 1: Itgam-deficient mice have more production of proinflammatory cytokines when challenged with TLR ligands and are more susceptible to endotoxic shock.
Figure 2: Itgam-deficient mice are more susceptible to E. coli. infection and more resistant to L. monocytogenes infection.
Figure 3: Itgam deficiency enhances TLR-triggered production of proinflammatory cytokines and type I interferon in macrophages through increased activation of NF-κB and IRF3.
Figure 4: CD11b negatively regulates TLR-triggered inflammatory responses by enhancing activation of Src and Syk.
Figure 5: Activated Syk interacts with and phosphorylates MyD88 and TRIF.
Figure 6: Activated Syk promotes Cbl-b-mediated degradation of MyD88 and TRIF by inducing phosphorylation of Tyr227 on MyD88 and Tyr375 on TRIF.
Figure 7: Overexpression of phosphorylation-defective mutants of MyD88 and TRIF promotes the production of proinflammatory cytokines and IFN-β by amplifying TLR signaling.
Figure 8: An active CD11b signal inhibits TLR-triggered inflammatory responses by promoting degradation of MyD88 and TRIF in macrophages.

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Acknowledgements

We thank H. An, M. Zhang, T. Zhang, J. Hou, X. Liu and T. Chen for discussions; F. He for statistical assistance; Y. Li and M. Jin for technical assistance; C. Ni for pathological analysis; S. Akira (Research Institute for Microbial Diseases, Osaka University) for Myd88-deficient mice; H. Yao (Zhejiang University) for E. coli; H. Shen (University of Pennsylvania School of Medicine) for L. monocytogenes; and M. Liu (Shanghai Institute of Biochemistry and Cell Biology) for lentiviral vector. Supported by the National Natural Science Foundation of China (30721091 and 30572121), the National Key Basic Research Program of China (2007CB512403 and 2010CB911903) and the Shanghai Committee of Science and Technology.

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Authors and Affiliations

  1. National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China

    Chaofeng Han, Sheng Xu, Haibo Liu, Nan Li & Xuetao Cao

  2. Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China

    Jing Jin & Xuetao Cao

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Contributions

X.C. and C.H. designed the experiments; C.H., J.J., S.X., H.L. and N.L. did the experiments; and X.C. and C.H. analyzed data and wrote the manuscript.

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Correspondence to Xuetao Cao.

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Han, C., Jin, J., Xu, S. et al. Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b. Nat Immunol 11, 734–742 (2010). https://doi.org/10.1038/ni.1908

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