A toll-like receptor 2-responsive lipid effector pathway protects mammals against skin infections with gram-positive bacteria

Philippe Georgel, Karine Crozat, Xavier Lauth, Evgenia Makrantonaki, Holger Seltmann, Sosathya Sovath, Kasper Hoebe, Xin Du, Sophie Rutschmann, Zhengfan Jiang, Timothy Bigby, Victor Nizet, Christos C. Zouboulis, Bruce Beutler

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164 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4512-4521
Number of pages10
JournalInfection and Immunity
Volume73
Issue number8
DOIs
StatePublished - Aug 2005

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ASJC Scopus subject areas

  • Immunology

Cite this

Georgel, P., Crozat, K., Lauth, X., Makrantonaki, E., Seltmann, H., Sovath, S., Hoebe, K., Du, X., Rutschmann, S., Jiang, Z., Bigby, T., Nizet, V., Zouboulis, C. C., & Beutler, B. (2005). A toll-like receptor 2-responsive lipid effector pathway protects mammals against skin infections with gram-positive bacteria. Infection and Immunity, 73(8), 4512-4521. https://doi.org/10.1128/IAI.73.8.4512-4521.2005