R-form LPS, the master key to the activation ofTLR4/MD-2-positive cells.
Lipopolysaccharide (endotoxin, LPS) is a major recognition marker for the detection of gram-negative bacteria by the host and a powerful initiator of the inflammatory response to infection. Using S- and R-form LPS from wild-type and R-mutants of Salmonella and E. coli, we show that R-form LPS readily activates mouse cells expressing the signaling receptor Toll-like receptor 4/myeloid differentiation protein 2 (TLR4/MD-2), while the S-form requires further the help of the LPS-binding proteins CD14 and LBP, which limits its activating capacity. Therefore, the R-form LPS under physiological conditions recruits a larger spectrum of cells in endotoxic reactions than S-form LPS. We also show that soluble CD14 at high concentrations enables CD14-negative cells to respond to S-form LPS. The presented in vitro data are corroborated by an in vivo study measuring TNF-alpha levels in response to injection of R- and S-form LPS in mice. Since the R-form LPS constitutes ubiquitously part of the total LPS present in all wild-type bacteria its contribution to the innate immune response and pathophysiology of infection is much higher than anticipated during the last half century.
Huber
Michael
M
Molecular Immunology, Institute for Biology III, Albert-Ludwigs University Freiburg, Freiburg, Germany. huberm@immunbio.mpg.de
Kalis
Christoph
C
Keck
Simone
S
Jiang
Zhengfan
Z
Georgel
Philippe
P
Du
Xin
X
Shamel
Louis
L
Sovath
Sosathya
S
Mudd
Suzanne
S
Beutler
Bruce
B
Galanos
Chris
C
Freudenberg
Marina A
MA
D000818:Animals; D002478:Cells, Cultured; D004926:Escherichia coli / Q000235:genetics / Q000276:immunology*; D016905:Gram-Negative Bacterial Infections / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology* / Q000494:pharmacology; D051218:Lymphocyte Antigen 96 / Q000172:deficiency / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D012475:Salmonella / Q000235:genetics / Q000276:immunology*; D013045:Species Specificity; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000276:immunology*
D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4