Article

Association of SIGNR1 with TLR4-MD-2 enhances signal transduction by recognition of LPS in gram-negative bacteria.

Laboratory of Immunobiology, Department of Animal Development and Physiology, Graduate School of Biostudies, Kyoto University, Kitashirakawa-Oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan.
International Immunology (impact factor: 3.41). 08/2005; 17(7):827-36. DOI:10.1093/intimm/dxh264 pp.827-36
Source: PubMed

ABSTRACT SIGNR1, a member of a new family of mouse C-type lectins, is expressed at high levels in macrophages (Mphi) within the splenic marginal zone, lymph node medulla, and in some strains, in peritoneal cavity. We previously reported that SIGNR1 captures gram-negative bacteria, such as Escherichia coli and Salmonella typhimurium, as well as Candida albicans. We have now investigated the precise ligands and innate responses that involve SIGNR1. The interaction of SIGNR1 with FITC-dextran and E. coli was completely inhibited by LPS from E. coli and Salmonella minnesota. Using LPS from various types of rough mutants of Salmonella, we found that SIGNR1 primarily recognizes oligosaccharides in the non-reductive end of the LPS core region. In transfectants, expression of SIGNR1 enhanced the oligomerization of Toll-like receptor (TLR) 4 molecules as well as the degradation of IkappaB-alpha after stimulation with E. coli under low-serum conditions. The enhanced TLR4 oligomerization was inhibited by pre-treatment of the cells with anti-SIGNR1 mAb or with mannan. A physical association between SIGNR1 and the TLR4-MD-2 complex was also observed by immunoprecipitation. Finally, we found that transfection of SIGNR1 into the macrophage-like RAW264.7 cells resulted in significant augmentation of cytokine production. These results suggest that SIGNR1 associates with TLR4 to capture gram-negative bacteria and facilitate signal transduction to activate innate M responses.

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Keywords

activate innate M responses
 
anti-SIGNR1 mAb
 
capture gram-negative bacteria
 
E. coli
 
enhanced TLR4 oligomerization
 
Escherichia coli
 
involve SIGNR1
 
low-serum conditions
 
LPS core region
 
lymph node medulla
 
macrophage-like RAW264.7 cells
 
mouse C-type lectins
 
new family
 
non-reductive end
 
precise ligands
 
significant augmentation
 
SIGNR1 associates
 
SIGNR1 captures gram-negative bacteria
 
splenic marginal zone
 
TLR4-MD-2 complex
 

Koji Nagaoka