CD14 is required for MyD88-independent LPS signaling.
The recessive mutation 'Heedless' (hdl) was detected in third-generation N-ethyl-N-nitrosourea-mutated mice that showed defective responses to microbial inducers. Macrophages from Heedless homozygotes signaled by the MyD88-dependent pathway in response to rough lipopolysaccharide (LPS) and lipid A, but not in response to smooth LPS. In addition, the Heedless mutation prevented TRAM-TRIF-dependent signaling in response to all LPS chemotypes. Heedless also abolished macrophage responses to vesicular stomatitis virus and substantially inhibited responses to specific ligands for the Toll-like receptor 2 (TLR2)-TLR6 heterodimer. The Heedless phenotype was positionally ascribed to a premature stop codon in Cd14. Our data suggest that the TLR4-MD-2 complex distinguishes LPS chemotypes, but CD14 nullifies this distinction. Thus, the TLR4-MD-2 complex receptor can function in two separate modes: one in which full signaling occurs and one limited to MyD88-dependent signaling.
Jiang
Zhengfan
Z
Department of Immunology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, USA.
Georgel
Philippe
P
Du
Xin
X
Shamel
Louis
L
Sovath
Sosathya
S
Mudd
Suzanne
S
Huber
Michael
M
Kalis
Christoph
C
Keck
Simone
S
Galanos
Chris
C
Freudenberg
Marina
M
Beutler
Bruce
B
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D000950:Antigens, Ly / Q000737:chemistry / Q000378:metabolism; D066298:In Vitro Techniques; D007370:Interferon Type I / Q000096:biosynthesis; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity*; D051218:Lymphocyte Antigen 96; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D046912:Multiprotein Complexes; D009154:Mutation; D053594:Myeloid Differentiation Factor 88; D011971:Receptors, Immunologic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4; D014721:Vesicular stomatitis Indiana virus / Q000472:pathogenicity
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D000950:Antigens, Ly; D007370:Interferon Type I; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; D046912:Multiprotein Complexes; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011971:Receptors, Immunologic; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4