Abstract
Integrins are critical for the migration and function of leukocytes in inflammation. However, the interaction between integrin alpha(M) (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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / immunology*
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Adaptor Proteins, Signal Transducing / metabolism
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Adaptor Proteins, Vesicular Transport / immunology
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Adaptor Proteins, Vesicular Transport / metabolism
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Animals
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CD11b Antigen / immunology*
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Enzyme Activation
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Escherichia coli / immunology
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Escherichia coli Infections / immunology
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Gene Expression Regulation, Enzymologic
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Immunity, Innate / immunology
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Inflammation / enzymology
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Inflammation / immunology*
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Intracellular Signaling Peptides and Proteins / immunology*
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Intracellular Signaling Peptides and Proteins / metabolism
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Macrophages / immunology
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Mice
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Mice, Knockout
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Myeloid Differentiation Factor 88 / immunology
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Myeloid Differentiation Factor 88 / metabolism
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Protein-Tyrosine Kinases / immunology*
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins c-cbl / immunology*
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Proto-Oncogene Proteins c-cbl / metabolism
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Signal Transduction
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Syk Kinase
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Toll-Like Receptors / immunology*
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src-Family Kinases / immunology
Substances
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport
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CD11b Antigen
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Cblb protein, mouse
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Intracellular Signaling Peptides and Proteins
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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TICAM-1 protein, mouse
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Toll-Like Receptors
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Proto-Oncogene Proteins c-cbl
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Protein-Tyrosine Kinases
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Syk Kinase
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Syk protein, mouse
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src-Family Kinases