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

Area of Science:

• Microbiology
• Genetics
• Immunology

Background:

• The flake (flk) mutation in mice impairs clearance of skin infections caused by Gram-positive bacteria like Streptococcus pyogenes and Staphylococcus aureus.
• These bacteria activate innate immune responses via Toll-like receptor 2 (TLR2).

Purpose of the Study:

• To identify the genetic basis of the flake mutation.
• To elucidate the role of fatty acids and TLR2 signaling in antimicrobial defense.

Main Methods:

• Positional cloning and sequencing to identify the mutated gene.
• Phenotypic analysis of flake homozygotes, including sebum production and fatty acid synthesis.
• In vitro and in vivo experiments assessing bacterial clearance and the effect of monounsaturated fatty acids (MUFA).
• Analysis of stearoyl coenzyme A desaturase 1 (Scd1) gene expression in response to TLR2 signaling.

Main Results:

• The flake mutation is a novel allele of the stearoyl coenzyme A desaturase 1 (Scd1) gene.
• Flake homozygotes exhibit reduced sebum and lack bactericidal MUFAs (palmitoleate and oleate).
• TLR2 signaling strongly induces Scd1 transcription in normal mice and human sebocytes.
• Intradermal MUFA administration partially rescues the impaired bacterial clearance in flake mice.

Conclusions:

• Mammalian skin possesses a regulated, lipid-based antimicrobial pathway involving MUFAs.
• SCD1, regulated by TLR2, is crucial for producing these antimicrobial lipids.
• This pathway offers potential targets for treating Gram-positive bacterial infections.