TY - JOUR
T1 - A toll-like receptor 2-responsive lipid effector pathway protects mammals against skin infections with gram-positive bacteria
AU - Georgel, Philippe
AU - Crozat, Karine
AU - Lauth, Xavier
AU - Makrantonaki, Evgenia
AU - Seltmann, Holger
AU - Sovath, Sosathya
AU - Hoebe, Kasper
AU - Du, Xin
AU - Rutschmann, Sophie
AU - Jiang, Zhengfan
AU - Bigby, Timothy
AU - Nizet, Victor
AU - Zouboulis, Christos C.
AU - Beutler, Bruce
PY - 2005/8
Y1 - 2005/8
N2 - flake (flk), an N-ethyl-N-nitrosourea-induced recessive germ line mutation of C57BL/6 mice, impairs the clearance of skin infections by Streptococcus pyogenes and Staphylococcus aureus, gram-positive pathogens that elicit innate immune responses by activating Toll-like receptor 2 (TLR2) (K. Takeda and S. Akira, Cell. Microbiol. 5:143-153, 2003). Positional cloning and sequencing revealed that flk is a novel allele of the stearoyl coenzyme A desaturase 1 gene (Scd1). flake homozygotes show reduced sebum production and are unable to synthesize the monounsaturated fatty acids (MUFA) palmitoleate (C 16:1) and oleate (C18:1), both of which are bactericidal against gram-positive (but not gram-negative) organisms in vitro. However, intradermal MUFA administration to S. aureus-infected mice partially rescues the flake phenotype, which indicates that an additional component of the sebum may be required to improve bacterial clearance. In normal mice, transcription of Scd1-a gene with numerous NF-κB elements in its promoter-is strongly and specifically induced by TLR2 signaling. Similarly, the SCD1 gene is induced by TLR2 signaling in a human sebocyte cell line. These observations reveal the existence of a regulated, lipid-based antimicrobial effector pathway in mammals and suggest new approaches to the treatment or prevention of infections with gram-positive bacteria.
AB - flake (flk), an N-ethyl-N-nitrosourea-induced recessive germ line mutation of C57BL/6 mice, impairs the clearance of skin infections by Streptococcus pyogenes and Staphylococcus aureus, gram-positive pathogens that elicit innate immune responses by activating Toll-like receptor 2 (TLR2) (K. Takeda and S. Akira, Cell. Microbiol. 5:143-153, 2003). Positional cloning and sequencing revealed that flk is a novel allele of the stearoyl coenzyme A desaturase 1 gene (Scd1). flake homozygotes show reduced sebum production and are unable to synthesize the monounsaturated fatty acids (MUFA) palmitoleate (C 16:1) and oleate (C18:1), both of which are bactericidal against gram-positive (but not gram-negative) organisms in vitro. However, intradermal MUFA administration to S. aureus-infected mice partially rescues the flake phenotype, which indicates that an additional component of the sebum may be required to improve bacterial clearance. In normal mice, transcription of Scd1-a gene with numerous NF-κB elements in its promoter-is strongly and specifically induced by TLR2 signaling. Similarly, the SCD1 gene is induced by TLR2 signaling in a human sebocyte cell line. These observations reveal the existence of a regulated, lipid-based antimicrobial effector pathway in mammals and suggest new approaches to the treatment or prevention of infections with gram-positive bacteria.
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U2 - 10.1128/IAI.73.8.4512-4521.2005
DO - 10.1128/IAI.73.8.4512-4521.2005
M3 - Article
C2 - 16040962
AN - SCOPUS:23344436144
SN - 0019-9567
VL - 73
SP - 4512
EP - 4521
JO - Infection and immunity
JF - Infection and immunity
IS - 8
ER -