Combinational clustering of receptors following stimulation by bacterial products determines lipopolysaccharide responses.
The innate immune system has the capacity to recognize a wide range of pathogens based on conserved PAMPs (pathogen-associated molecular patterns). In the case of bacterial LPS (lipopolysaccharide) recognition, the best studied PAMP, it has been shown that the innate immune system employs at least three cell-surface receptors: CD14, TLR4 (Toll-like receptor 4) and MD-2 protein. CD14 binds LPS from Enterobacteriaceae and then transfers it to MD-2, leading to TLR4 aggregation and signal transduction. LPS analogues such as lipid IVa seem to act as LPS antagonists in human cells, but exhibit LPS mimetic activity in mouse cells. Although TLR4 has been shown to be involved in this species-specific discrimination, the mechanism by which this is achieved has not been elucidated. The questions that remain are how the innate immune system can discriminate between LPS from different bacteria as well as different LPS analogues, and whether or not the structure of LPS affects its interaction with the CD14-TLR4-MD-2 cluster. Is it possible that the 'shape' of LPS induces the formation of different receptor clusters, and thus a different immune response? In the present study, we demonstrate using biochemical as well as fluorescence-imaging techniques that different LPS analogues trigger the recruitment of different receptors within microdomains. The composition of each receptor cluster as well as the number of TLR4 molecules that are recruited within the cluster seem to determine whether an immune response will be induced or inhibited.
Triantafilou
Martha
M
Infection and Immunity Group, School of Life Sciences, University of Sussex, JMS Building, Falmer, Brighton BN1 9QG, UK. K.Triantafilou@sussex.ac.uk
Brandenburg
Klaus
K
Kusumoto
Shoichi
S
Fukase
Koichi
K
Mackie
Alan
A
Seydel
Ulrich
U
Triantafilou
Kathy
K
D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism / Q000502:physiology; D016466:CHO Cells / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D006224:Cricetinae; D036681:Fluorescence Recovery After Photobleaching / Q000379:methods; D006801:Humans; D008050:Lipid A / Q000031:analogs & derivatives / Q000276:immunology; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology*; D051218:Lymphocyte Antigen 96; D020935:MAP Kinase Signaling System / Q000502:physiology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D021962:Membrane Microdomains / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D011940:Receptor Aggregation / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014162:Transfection / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000954:Antigens, Surface; C495377:LY96 protein, human; D008050:Lipid A; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases