Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b.
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.
Han
Chaofeng
C
National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China.
Jin
Jing
J
Xu
Sheng
S
Liu
Haibo
H
Li
Nan
N
Cao
Xuetao
X
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology* / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology / Q000378:metabolism; D000818:Animals; D039481:CD11b Antigen / Q000276:immunology*; D004789:Enzyme Activation; D004926:Escherichia coli / Q000276:immunology; D004927:Escherichia coli Infections / Q000276:immunology; D015971:Gene Expression Regulation, Enzymologic; D007113:Immunity, Innate / Q000276:immunology; D007249:Inflammation / Q000201:enzymology / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000276:immunology* / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D000072377:Syk Kinase; D051193:Toll-Like Receptors / Q000276:immunology*; D019061:src-Family Kinases / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D039481:CD11b Antigen; D047908:Intracellular Signaling Peptides and Proteins; D053594:Myeloid Differentiation Factor 88; D011505:Protein-Tyrosine Kinases; D050721:Proto-Oncogene Proteins c-cbl; D000072377:Syk Kinase; D051193:Toll-Like Receptors; D019061:src-Family Kinases; C118387:Cblb protein, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C000606897:Syk protein, mouse