Siglec-E Negatively Regulates the Activation of TLR4 by Controlling Its Endocytosis.
TLR4 signaling is critical for providing effective immune protection, but it must be tightly controlled to avoid inflammation-induced pathology. Previously, we reported extensive and direct interactions between TLR and Siglec families of pattern recognition receptors. In this study, we examined the biological significance of this interaction during infection. We show that Siglec-E is required for Escherichia coli-induced endocytosis of TLR4. Siglec-E-deficient dendritic cells infected with E. coli fail to internalize TLR4. This leads to sustained TLR4 on the cell surface and activation of NF-κB and MAPK p38, resulting in high levels of TNF-α and IL-6 compared with wild-type dendritic cells. In contrast to the signaling events occurring at the plasma membrane, as a result of the inability to internalize TLR4, Siglec-E-deficient dendritic cells were also defective for TRIF-mediated IFN-β production in response to E. coli infection. Furthermore, we found that accumulation of ubiquitinated TLR4 and binding of E3 ubiquitin ligase Triad3A to TLR4 was increased significantly in bone marrow-derived dendritic cells from wild-type mice, but not from Siglec-E-deficient mice, after E. coli infection. This represents a newly discovered mechanism that regulates the signaling of TLR4 during E. coli infection.
Children's Foundation Research Institute, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38103.
Yin
Y
Wu
Children's Foundation Research Institute, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38103.
Dongren
D
Ren
Children's Foundation Research Institute, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38103 Gchen14@uthsc.edu.
Guo-Yun
GY
Chen
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism*; D002478:Cells, Cultured; D004705:Endocytosis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; C422908:Siglece protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4